WO2006119713A2 - Compuestos con acción antineoplásica y composiciones farmaceuticas que los contienen - Google Patents

Compuestos con acción antineoplásica y composiciones farmaceuticas que los contienen Download PDF

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Publication number
WO2006119713A2
WO2006119713A2 PCT/CU2006/000002 CU2006000002W WO2006119713A2 WO 2006119713 A2 WO2006119713 A2 WO 2006119713A2 CU 2006000002 W CU2006000002 W CU 2006000002W WO 2006119713 A2 WO2006119713 A2 WO 2006119713A2
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Prior art keywords
phosphorylation
chemical compounds
compounds
substrate
chemical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CU2006/000002
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English (en)
French (fr)
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WO2006119713A3 (es
Inventor
Rolando Eduardo Rodriguez Fernandez
Roberto Vera Alvarez
Ania De La Nuez Veulens
Yuliet Mazola Reyes
Silvio Ernesto PEREA RODRÍGUEZ
Boris Ernesto Acevedo Castro
Alexis Musacchio Lasa
Raimundo UBIETA GÓMEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centro de Ingenieria Genetica y Biotecnologia CIGB
Original Assignee
Centro de Ingenieria Genetica y Biotecnologia CIGB
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Application filed by Centro de Ingenieria Genetica y Biotecnologia CIGB filed Critical Centro de Ingenieria Genetica y Biotecnologia CIGB
Priority to BRPI0608806-6A priority Critical patent/BRPI0608806A2/pt
Priority to AU2006246204A priority patent/AU2006246204B2/en
Priority to KR1020077028594A priority patent/KR20080008407A/ko
Priority to CN2006800219987A priority patent/CN101203522B/zh
Priority to DK06753157.4T priority patent/DK1892245T3/en
Priority to MX2007014216A priority patent/MX2007014216A/es
Priority to US11/920,031 priority patent/US8748411B2/en
Priority to JP2008510389A priority patent/JP5117377B2/ja
Priority to CA2607298A priority patent/CA2607298C/en
Priority to EP06753157.4A priority patent/EP1892245B1/en
Priority to ES06753157.4T priority patent/ES2550959T3/es
Publication of WO2006119713A2 publication Critical patent/WO2006119713A2/es
Publication of WO2006119713A3 publication Critical patent/WO2006119713A3/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07C255/00—Carboxylic acid nitriles
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    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
    • C07C281/12—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being part of a ring other than a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/38—Nitrogen atoms
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    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/224—Phosphorus triamides

Definitions

  • the present invention falls within the field of molecular pharmacology and specifically with oncology, specifically with chemical compounds obtained by molecular modeling in silico with cytotoxic action and antitumor effect by blocking the phosphorylation site described for the substrates of The enzyme Casein Kinase 2 (CK2) by direct or indirect interaction and the pharmaceutical compositions containing them.
  • CK2 Casein Kinase 2
  • CK2 is a serine / threonine enzyme that is involved in the increase of cell proliferation and its intracellular location is fundamentally nuclear during the process of malignant transformation (Tawfic S., Yu S., Wang H., Faust R., Davis A ., Ahmed K. (2001) Protein kinase CK2 signal in neoplasia. Histol. Histopathol. 16: 573-582).
  • HIV Human Immunodeficiency Virus
  • HCV Hepatitis C Virus
  • CK2-mediated phosphorylation is a biochemical event that constitutes a potential target for the therapeutic intervention of cancer and that inhibitors of such an event may constitute candidates with perspectives for the treatment of this entity.
  • different groups in the world have developed strategies to inhibit CK2-mediated phosphorylation with the use of two experimental approaches: a) The direct inhibition of the enzyme, or b) The phosphorylation site block within the acidic domain described for CK2 substrates.
  • a direct enzyme inhibitor such as 4, 5, 6, 7- tetrabromobenzotriazole (TBB) has been tested as an inducer of apoptosis and caspase-dependent degradation in JurKatt cells in the micromolar concentration range (Ruzzene M. , Penzo D., Pinna L.
  • Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem J., 364: 41-47).
  • TLB Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole
  • peptides described in these reports have the limitation that they are not capable of penetrating into the cell by themselves, thus requiring fusion with another type of peptide with intrinsically permeable ability.
  • peptides compared to small molecules have problems with the n-live stability within the circulation, as well as with their oral administration and / or cellular penetration, aspects in which small molecules overcome them (Ludger Wess, Isogenica: Improving peptides, Biocentury October 25, 2004).
  • Other limitations of peptide forms as therapeutic Io constitutes its rapid clearance as well as its potential immunogenic capacity and the economic cost per therapeutic dose, generally higher than drugs.
  • the present invention describes, for the first time, chemical molecules that inhibit phosphorylation by direct or indirect interaction with the phosphorylation site of the substrates for CK2, as well as The induction of cytotoxicity and antitumor effect in experimental models of cancer.
  • the chemical compounds of the invention have a structure that allows them to meet one or more of the following requirements:
  • A causes the binding of the compounds to the phosphorylation domain or its environment in the substrate of the CK2, directly or indirectly blocking the binding of the enzyme to the substrate.
  • B causes the binding of the compounds to the phosphorylation domain of the substrate of Ia
  • C causes the binding of the compounds to the substrate protein of the CK2, causing a conformational change in the phosphorylation domain, its environment or both, directly or indirectly that prevents the binding of the CK2 or the transfer of the phosphate group to The phosphoceptor serine.
  • the invention relates to chemical molecules which have a chemical structure defined by the occurrence, in any part of the molecule, consecutively of the following elements, with the indicated hybridization characteristics, linked together, grouped together. in the following five structural classes:
  • the invention also includes any homologous variant of the above compounds.
  • a homologous variant is understood as any molecule of a chemical nature similar or not to those described here, whose structure allows the same effect of the compounds described herein, and its result is to inhibit the phosphorylation of CK2 substrates.
  • the pharmaceutical composition contains one or more of the chemical compounds or their pharmaceutically acceptable salts, as well as pharmaceutically acceptable excipients or vehicles. Also part of the present invention is the use of chemical compounds, for the manufacture of medicaments for the inhibition of the proliferation of tumor cells in vitro, in vivo or in devices associated with the body and for the treatment of cancer in living beings and others. diseases where CK2 has a pathological role.
  • the chemical molecules described were defined by their ability to inhibit the phosphorylation of the minimum amino acid sequence S / TXXE / D, X being preferably a different amino acid of the Usina or Arginine type, although other proteins are not ruled out, which do not have this consensus sequence but which are also phosphorylated by CK2, bind these types of compounds and their phosphorylation is inhibited by them.
  • X being preferably a different amino acid of the Usina or Arginine type, although other proteins are not ruled out, which do not have this consensus sequence but which are also phosphorylated by CK2, bind these types of compounds and their phosphorylation is inhibited by them.
  • exhaustive molecular modeling of the consensus phosphorylation site described for this enzyme was performed (Meggio F., Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2. FASEB J.
  • the chemical compounds described are equally effective in their ability to inhibit the phosphorylation event by CK2.
  • the chemical compounds described in the present invention produce cytotoxicity in a dose-dependent manner in tumor cells of human origin without the need for coupling to intracellular penetration vehicles.
  • These Evidence corresponds to previous findings that demonstrate that chemical molecules are capable of penetrating into the cell and interacting with their respective targets (Meggio F, Pagano MA, Moro S, Zagotto G, Ruzzene M, Samo S 1 Cozza G, Bain J, Elliott M, Deana AD, Brunati AM, Pinna LA (2004) Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and ⁇ n vivo study. Biochemistry.
  • Figure 1 Antitumor effect of chemical compounds in human tumor models implanted in mice
  • Example 1 Selection of the compounds by molecular modeling in silico.
  • Example 2 Effect of the chemical compounds described on the phosphorylation of a typical CK2 substrate.
  • This assay consists of an in vitro phosphorylation reaction where the E7 oncoprotein of Human Papillomavirus type 16 (HPV-16) expressed in E. CoIi was used as a fusion protein to Glutathione S-Transferase (GST). Subsequently, E7-GST was purified by affinity chromatography using Glutathione-Sepharose (Pharmacia). Before the enzymatic reaction, the E7-GST was pre-incubated with different concentrations of the chemical compounds mentioned in the invention for one hour at 37 0 C.
  • the reaction mixture is carried out in 50 ⁇ l of Tris buffer: 25 mM HCL pH 7.5, 1 ⁇ Ci of 32 P- ⁇ ATP, 100 ⁇ M ATP, 40 ⁇ l of the resin containing E7-GST, 0.2 M NaCI, 10 mM MgCI and 1 unit of Ia CK2 enzyme (Promega).
  • the reaction was incubated at 37 0 C for 40 minutes.
  • three washes of the resin are performed with 0.5 ml of the reaction buffer and finally the phosphorylation level of the E7-GST is analyzed in a 10% PAGE electrophoresis.
  • the visualization of the phosphorylated protein was carried out by developing X-ray plates previously exposed with the dry gel.
  • the quantification of the phosphorylation of E7 was performed by densitometry analysis of the respective plates. IC50 values were estimated from the respective dose-effect curves. The IC50 represents the concentration that inhibits 50% of the enzymatic activity. At the same time, the P15 cyclic peptide reported as a phosphorylation site inhibitor of CK2 substrates was included as a comparison control. The results observed in Table 2 indicate that the different chemical compounds described in this invention are effective inhibitors of a phosphorylation site typical of CK2 according to the IC50 values observed.
  • Example 3 Effect of the chemical compounds described on the consensus phosphorylation site of CK2.
  • This test consists of an in vito phosphorylation reaction where the RRREEETEEE sequence representing the consensus domain optimized for CK2 phosphorylation was used as a substrate.
  • phosphorylation substrate peptide Prior to the reaction of phosphorylation substrate peptide was incubated for one hour at 37 0 C with various chemical compounds described in the invention. Then, the reaction mixture was carried out in 50 ⁇ l of Tris buffer: 25 mM HCL pH 7.5, 1 ⁇ Ci of 32 P- ⁇ ATP, 100 ⁇ M ATP, 2 mg / ml of the substrate peptide, 0.2 M NaCI, 10 mM MgCI and 1 CK2 enzyme unit (Promega). The reaction was incubated at 37 0 C for 10 minutes.
  • Example 4 Effect of the chemical compounds of the present invention on human tumor cells.
  • H-125 cells from a Human Lung Carcinoma to Non-Small Cells were seeded in 96-well plates (Costar) at a density of 2x10 4 cells / ml in Dulbecco medium (DMEM) (Gibco) ) supplemented with Fetal Bovine Serum (Gibco).
  • DMEM Dulbecco medium
  • Fetal Bovine Serum Fetal Bovine Serum
  • Example 5 Antitumor effect of the chemical compounds of the invention in human tumor models implanted in nude mice.
  • nude female BaIbC mice between 6 and 8 weeks old were used.
  • 5,000,000 H-125 cells resuspended in 250 ⁇ l of PBS were inoculated in the dorsal region of the animals.
  • the direct administration of 200 ⁇ g of the compounds C32425, C33426 and C33427 was performed consecutively for 5 days.
  • the administration of chemical compounds is capable of producing a significant antitumor response.

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Abstract

Compuestos químicos obtenidos por modelación molecular in silico, y cuya estructura permite el bloqueo de la fosforilación mediante la interacción de dichos compuestos con el dominio de fosforilación o su entorno en los sustratos de la enzima Caseína Kinasa 2. La invención comprende además las composiciones farmacéuticas que contienen dichos compuestos y su uso en la preparación de medicamentos para el tratamiento de enfermedades relacionadas con procesos neoplásicos.

Description

COMPUESTOS CON ACCIÓN ANTINEOPLÁSICA Y COMPOSICIONES FARMACÉUTICAS QUE LOS CONTIENEN.
Campo de Ia técnica La presente invención se encuadra dentro del campo de Ia farmacología molecular y en concreto con Ia oncología, específicamente con compuestos químicos obtenidos por modelación molecular in silico con acción citotóxica y efecto antitumoral al bloquear el sitio de fosforilación descrito para los sustratos de Ia enzima Caseína Kinasa 2 (CK2) mediante interacción directa o indirecta y las composiciones farmacéuticas que los contenga.
Estado de Ia técnica anterior
La CK2 es una enzima serina/treonina que está involucrada en el incremento de Ia proliferación celular y su localización intracelular es fundamentalmente nuclear durante el proceso de transformación maligna (Tawfic S., Yu S., Wang H., Faust R., Davis A., Ahmed K. (2001) Protein kinase CK2 signal in neoplasia. Histol. Histopathol. 16:573-582). Así mismo, algunas proteínas virales claves en Ia patogenia del Virus de Ia Inmnunodeficiencia Humana (VIH) y del Virus de Ia Hepatitis C (VHC) han sido reportadas como sustratos para CK2 (Meggio F., Marín O., Boschetti M., Samo S., Pinna LA. (2001) Mol CeII Biochem 227:145-151 ; Franck N., Le Seyec J., Guguen-Guillouzo C1 Erdtmann L. (2005) Hepatitis C virus NS2 protein is phosphorylated by the protein kinase CK2 and targeted for degradation to the proteasome. J Virol. 79:2700-2008) Hallazgos de diferentes grupos en el mundo han confirmado Ia existencia de niveles elevados de CK2 en diversos tumores sólidos de origen epitelial en ordenes entre 3 y 7 veces respecto al tejido normal (Tawfic S., Yu S., Wang H., Faust R., Davis A., Ahmed K. (2001) Protein kinase CK2 sígnal in neoplasia. Histol Histopatol. 16:573- 582; Faust R.A., Gapany M., et al (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cáncer Letters 101 :31-35), además de que Ia actividad de fosforilación por esta enzima es un evento celular importante en Ia transformación maligna y constituye un marcador de progresión del tumor (Seldin D.C., Leder P. (1995) Casein Kinase llα transgene-induced murine lymphoma: relation to theileroiosis in cattle. Science 267:894-897). Por otro lado, Ia sobre-expresión de CK2 en animales trangénicos conlleva a Ia tumorigenesis de las glándulas mamarias a través del incremento de Ia cascada de señalización Wnt/beta-catenina en las células epiteliales mamarias (Landesman-Bollag E., Romien-Mourez R., et al (2001) Protein Kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247-3257). Hallazgos recientes han sugerido también que Ia enzima CK2 juega un papel esencial en procesos como Ia remodelación de Ia cromatina (Barz T., Ackenmann K., Dubois G., EiIs R., Pyerin W. (2003) Genome-wide expression screens indícate a global role for protein kinase CK2 in chromatin remodeling. J Cell Sci. 116:1563-1577) y el mantenimiento de Ia viabilidad celular (Unger G. M., Davis A.T., Slaton J.W., Ahmed K. (2004) Protein kinase CK2 as regulador of cell survival: implications for cáncer therapy. Curr Cáncer Drug Targets, 4:77-84). Así mismo, de connotada implicación para el proceso de desarrollo del cáncer han sido los hallazgos que demuestran que Ia fosforilación mediada por CK2 constituye una señal fuerte para la protección frente al fenómeno de apoptosis, razón por Ia cual se considera esta enzima como un mediador antiapoptótico en Ia fisiología celular (Ahmed K., Gerber D. A., Cochet C. (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell BIoI, 12:226-229; Torres J., Rodríguez J., et al (2003) Phosphorylation- regulated cleavage of the tumor suppressor PTEN by caspase-3: ¡mplicatíons for the control of protein stability and PTEN-protein interactions. J BIoI Chem, 278:30652- 60).
Sobre Ia base de los hallazgos anteriormente descritos se confirma que Ia fosforilación mediada por CK2 es un evento bioquímico que constituye un blanco potencial para Ia intervención terapéutica del cáncer y que inhibidores de tal evento, pueden constituir candidatos con perspectivas para el tratamiento de esta entidad. Hasta el momento diferentes grupos en el mundo han desarrollado estrategias para inhibir Ia fosforilación mediada por CK2 con el uso de dos acercamientos experimentales: a) La inhibición directa de Ia enzima, o b) El bloqueo del sitio de fosforilación dentro del dominio acídico descrito para los sustratos de CK2. En ambos procedimientos, los autores han demostrado el concepto de que Ia inhibición del evento de fosforilación mediado por esta kinasa conlleva a Ia inducción de apoptosis de células tumorales lo cual constituyen resultados de validación experimental de CK2 como blanco de interés en el desarrollo de fármacos para el tratamiento del cáncer. Por ejemplo, un inhibidor directo de Ia enzima como es el 4, 5, 6, 7- tetrabromobenzotriazole (TBB) ha sido probado como inductor de apoptosis y de degradación dependiente de caspasas en células JurKatt en el rango de concentración micromolar (Ruzzene M., Penzo D., Pinna L. (2002) Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem J., 364:41-47). Así mismo, mediante Ia inhibición de Ia expresión de Ia enzima empleando oligonucleotidos antisentido se ha demostrado un efecto apoptótico in vitro, así como acción antitumoral en un modelo experimental de cáncer en ratones (Guo C1 Yu S., et al. (2001) A potential role of nuclear matrix- associated protein kinase CK2 in protection against drug-induced apoptosis ¡n cáncer cells. J Biol Chem, 276:5992-5999; Slaton J.W., et al. (2004) Induction of apoptosis by antisense CK2 in human prostate cáncer xenograft model. Mol Cáncer Res. 2:712-721). Otros inhibidores del sitio de unión al ATP han sido descritos para Ia CK2 entre los cuales se encuentran derivados de antraquinonas, flavonoides y compuestos derivados del azabenzimidazol halogenado (Sarno S., et al. (2002) Toward the rational design of protein kinase casein kinase-2 inhibitors. Pharmacol Therapeutics 93:159-168). De igual forma se ha reportado Ia identificación de un inhibidor selectivo de Ia CK2 mediante enlazamiento molecular de alto flujo que resulto ser el acido 5-oxo-5,6-dihidroindolo(1,2-a)quinazolin-7-yl=acético (IQA) (Vangrevelinghe E., et al. (2003) Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1 ,2- a)quinazolin-7-yl]acetic acid (IQA). J Med Chem. 46:2556-2662). Tales compuestos han mostrado su efecto inhibitorio de Ia actividad enzimática in vitro en valores de Concentración Inhibitoria 50 (CI50) en el rango micromolar sin embargo, no se han reportado evidencias de eficacia antitumoral in vivo de dichos inhibidores de CK2 en modelos experimentales de cáncer.
El otro acercamiento descrito para interferir el proceso de fosforilación mediado por CK2 ha sido mediante el bloqueo del sitio de fosforilación dentro del dominio acídico encontrado en los sustratos de esta enzima. En Ia solicitud de patente WO 03/054002 y el trabajo de Perea S. E., et al. (2004) Antitumor effect of a novel proapoptotic peptide impairing the phosphorylation by the protein kinase CK2. Cáncer Res. 64:7127-7129, se limitan a proponer el uso de una familia de péptidos cíclicos que bloquean Ia fosforilación del sustrato de CK2 in vitro y muestran citotoxicidad en células tumorales y efecto antitumoral en modelos preclínicos de cáncer. Sin embargo, los péptidos descritos en esos reportes presentan Ia limitante de que no son capaces de penetrar por si solos al interior de Ia célula necesitando así de Ia fusión con otro tipo de péptido con capacidad intrínseca permeable. En general, los péptidos comparados a moléculas pequeñas poseen problemas con Ia estabilidad ¡n-vivo dentro de Ia circulación, así como con su administración oral y/o penetración celular, aspectos en los cuales las moléculas pequeñas los superan (Ludger Wess, Isogenica: Improving peptides, Biocentury Octubre 25, 2004). Otras limitantes de las formas peptidicas como terapéuticos Io constituye su rápido aclaramiento así como su potencial capacidad inmunogénica y el costo económico por dosis terapéutica, generalmente superior a los fármacos.
Explicación de Ia invención.
Teniendo en cuenta las limitaciones potenciales de los péptidos cíclicos descritos como posibles agentes terapéuticos Ia presente invención describe, en efecto, por primera vez moléculas químicas que inhiben Ia fosforilación mediante interacción directa o indirecta con el sitio de fosforilación de los sustratos para CK2, así como Ia inducción de citotoxicidad y efecto antitumoral en modelos experimentales de cáncer. Los compuestos químicos de Ia invención tienen una estructura que les permite cumplir con uno o varios de los siguientes requerimientos:
A: provoca Ia unión de los compuestos al dominio de fosforilación o su entorno en el sustrato de Ia CK2, bloqueando directa o indirectamente Ia unión de Ia enzima al sustrato. B: provoca Ia unión de los compuestos al dominio de fosforilación del sustrato de Ia
CK2, permitiendo Ia unión de Ia enzima pero bloqueando directa o indirectamente Ia transferencia del grupo fosfato a Ia serina fosfoaceptora.
C: provoca Ia unión de los compuestos a Ia proteína sustrato de Ia CK2, provocando un cambio conformacional en el dominio de fosforilación, su entorno o ambos, de forma directa o indirecta que impide Ia unión de Ia CK2 o Ia transferencia del grupo fosfato a Ia serina fosfoaceptora.
De esta forma estos compuestos se caracterizan fundamentalmente por su capacidad de inhibición del evento bioquímico de fosforilación mediado por CK2. En una realización particular, Ia invención se refiere a moléculas químicas las cuales presentan una estructura química definida por Ia ocurrencia, en cualquier parte de Ia molécula, de manera consecutiva de los siguientes elementos, con las características de hibridación señaladas, enlazados entre sí, agrupados en las siguientes cinco clases estructurales:
I. N-[C(sp2)]iA3-N
II. N-[C(sp2)]il2-[C(sp3)]1 l2l3-N
III. N-[C(SpS)]L213-N
IV. N-C(SpZ)-[C(SpS)I1 ,2-C(sp2)-N
V. N-C(sp3)-[C(sp2)]i,2-C(sp3)-N
Compuestos pertenecientes a estas clases estructurales se muestran a continuación:
1.
,5,5-tr¡methylcyclohex-2-en-1-one sem¡carbazone
Figure imgf000006_0001
2.
m¡no-2,6-dihydroxypyrim¡din-5-yl)-W-¡sopropylth¡ourea
Figure imgf000006_0002
3.
-Λ/'-(2-furylmethyl)urea
Figure imgf000006_0003
4. arboxyethyl)amino]carbonyl}am¡no)propano¡c ac¡d
Figure imgf000007_0001
5.
loroethyl)-3-(cyanomethyl)urea
Figure imgf000007_0002
6.
(1/-/-indol-3-yl)acetone th¡osemicarbazone
Figure imgf000007_0003
7.
'-phosphoryltrihydrazinecarboxamide
Figure imgf000007_0004
8.
1-phenylhex-4-en-1-one semicarbazone
Figure imgf000007_0005
9. ¡oxoimidazolidin-4-yl)-3-(hydroxymethyl)urea
Figure imgf000008_0001
10.
Figure imgf000008_0002
11.
utyl-3-(2-chloroethyl)urea
Figure imgf000008_0003
loroethyl)-3-(1 -methyl-1 -phenylethyl)urea
Figure imgf000008_0004
13.
loroethyl)-3-[1,1-d¡methyl-2-(methylsulfonyl)ethyl]urea
Figure imgf000008_0005
14. no-Λ/-benzyl-2-(formylam¡no)-3-¡minopropanam¡de
Figure imgf000009_0001
15.
phenoxyacetone thiosem¡carbazone
Figure imgf000009_0002
16.
inoacetyl)am¡no]acetyl}amino)acetyl]am¡no}acetic ac¡d
Figure imgf000009_0003
17.
nzyloxy)carbonyl]am¡no}acetyl)(methyl)amiπo]acet¡c acid
Figure imgf000009_0004
18.
romopropanoyl)amino]acetyl}am¡no)acetic acid
Figure imgf000009_0005
19.
Figure imgf000010_0001
dithiosem¡carbazone
20.
minopropanoyl)am¡no]acetyl}amino)acetic acid
Figure imgf000010_0002
21.
luoro-3-(trifluoromethyl)phenyl]amino}acetohydrazide
Figure imgf000010_0003
22.
odophenyl)amino]acetohydrazide
Figure imgf000010_0004
23.
ihydroxypropyI)-2-(2-n¡tro-1W-im¡dazol-1-yl)propanamide
Figure imgf000010_0005
24. minoacetyl)amino]acetyl}amino)pentano¡c acid
Figure imgf000011_0001
25.
1 ,2-dithioxoethane-1 ,2-d¡yl)düm¡no]d¡acet¡c acid
Figure imgf000011_0002
26.
,NH ,NH
H2N' "NH ' NH2
C33426
Λ/-(2-am¡noethyl)-Λ/1-{2-[(2-am¡noethyI)am¡no]ethyl}ethane-1,2-d¡am¡ne
27.
1 ,4-dichlorobutane-2,3-diyl)d¡methanesulfonamide
Figure imgf000011_0003
28.
Figure imgf000011_0004
29. hydroxypyr¡midin-5-yl)sulfamic acid
Figure imgf000012_0001
30.
¡oxo¡midazolid¡n-4-yl)-Λ/-[3-(tr¡fluoromethyI)phenyl]methanesulfonamide
Figure imgf000012_0002
31.
roxyethyl)¡son¡cot¡nohydraz¡de
Figure imgf000012_0003
32.
ichIorobenzyl)th¡o]-6-hydroxypyr¡m¡dine-4-carboxyl¡c acid
Figure imgf000012_0004
33.
o-Λ/-ben2ylpropanamide
Figure imgf000012_0005
34. ysuccinohydraz¡de
Figure imgf000013_0001
35.
o-4-{[(benzyloxy)carbonyl]amino}-4-oxobutano¡c acid
Figure imgf000013_0002
36.
(phenyl)methyl]am¡no}benzamide
Figure imgf000013_0003
37.
Figure imgf000013_0004
S-(2-im¡no-2-{[2-(1-methyl-1H-benzimidazol-2-yl)ethyI]am¡no}ethyl) hydrogen thiosulfate
38. o-6-[(2-hydroxypropyl)amino]-5-nitropyrim¡d¡n-4-ol
Figure imgf000014_0001
39.
Figure imgf000014_0002
40.
(2-hydraz¡no-2-oxoethyl)-1 H-pyrrole-3-carboxylate
Figure imgf000014_0003
Estas moléculas fueron descritas para esta función mediante el modelado molecular exhaustivo del sitio de fosforilación consenso definido para esta enzima. (Meggio F.,
Pinna L.A. (2003) One-thousand-and-one sustrates of protein kinase CK2. The
FASEB J. 17:349-368) su validación por enlazamiento molecular a Ia proteína CK2 y el posterior análisis por acoplamiento molecular masivo de una base de datos de diversidad química generada en nuestro laboratorio conteniendo aproximadamente un millón doscientos mil compuestos.
La invención también incluye cualquier variante homologa de los compuestos anteriores. Se entiende por variante homologa a cualquier molécula de naturaleza química similar o no a los aquí descritos, cuya estructura permita realizar el mismo efecto de los compuestos aquí descritos, y su resultado sea inhibir Ia fosforilación de los sustratos de CK2. En otra realización preferida de Ia invención, Ia composición farmacéutica contiene uno o más de los compuestos químicos o sus sales farmacéuticamente aceptables, así como excipientes o vehículos farmacéuticamente aceptables. También es parte de Ia presente invención el uso de los compuestos químicos, para Ia manufactura de medicamentos para Ia inhibición de Ia proliferación de células tumorales in vitro, in vivo o en dispositivos asociados al cuerpo y para el tratamiento del cáncer en seres vivos y otras enfermedades donde Ia CK2 posea un papel patológico. Las moléculas químicas descritas se definieron por su capacidad de inhibir Ia fosforilación de Ia secuencia mínima de aminoácidos S/T-X-X-E/D siendo X preferiblemente algún aminoácido diferente del tipo Usina o Arginina, aunque no se descartan otras proteínas, que no poseen esta secuencia consenso pero que también son fosforiladas por CK2, unen este tipo de compuestos y su fosforilación se ve inhibida por ellos. Para Ia definición de los compuestos químicos descritos en Ia invención se realizó el modelado molecular exhaustivo del sitio de fosforilación consenso descrito para esta enzima (Meggio F., Pinna L.A. (2003) One-thousand-and-one sustrates of protein kinase CK2. The FASEB J. 17:349-368) su validación por enlazamiento molecular a Ia proteína CK2 y el posterior análisis por acoplamiento molecular masivo de una base de datos de diversidad química generada en nuestro laboratorio, conteniendo un millón doscientos mil compuestos. Los compuestos con valores calculados de energía de unión por encima de Ia media se seleccionaron como positivos para el primer ciclo, aplicándoles una segunda ronda de acoplamiento con valores más restrictivos de selección, y fueron analizados para extraer las regularidades estructurales, Ia estructura química de los compuestos seleccionados en el segundo ciclo fue optimizada para obtener valores mayores de energía de unión calculada. Tales compuestos fueron sintetizados, purificados utilizando Cromatografía Liquida, luego analizados por Espectrometría de Masas y Resonancia Magnético Nuclear así como Espectrofotometría Infrarroja y finalmente evaluados en cuanto a su efectividad in vitro e in vivo. De acuerdo con esta invención, los compuestos químicos descritos son igualmente eficaces en cuanto a su capacidad de inhibir el evento de fosforilación por CK2. Los compuestos químicos descritos en Ia presente invención producen citotoxicidad de una manera dosis-dependiente en células tumorales de origen humano sin necesidad de acoplamiento a vehículos de penetración ¡ntracelular. Estas evidencias se corresponden con hallazgos previos que demuestran que las moléculas químicas son capaces por si solas de penetrar al interior de Ia célula e interactuar con sus respectivos blancos (Meggio F, Pagano MA, Moro S, Zagotto G, Ruzzene M, Samo S1 Cozza G, Bain J, Elliott M, Deana AD, Brunati AM, Pinna LA (2004) Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and ¡n vivo study. Biochemistry. 43:12931-12936). De igual forma resulta de interés que los valores de CI50 encontrados para los compuestos químicos de Ia invención en los ensayos de citotoxicidad in vitro se encuentran en el rango nanomolar. Estos resultados demuestran una mayor eficacia anticelular de los compuestos químicos descritos en Ia invención respecto a los péptidos cíclicos previamente descritos como inhibidores del dominio de fosforilación de CK2. En concordancia con los resultados in vitro, los compuestos químicos de Ia presente invención ejercen un potente efecto antitumoral cuando estos se administran tanto por vía sistémica como localmente. De igual forma, se demostró que los compuestos químicos de Ia invención ejercen un efecto antitumoral en dosis tan bajas como 0.5 y 2 mg/Kg, Io cual representa una reducción de 10 a 20 veces de Ia dosis a Ia cual los péptidos cíclicos descritos anteriormente logran un efecto similar.
Breve descripción de las Figuras: Figura 1 : Efecto antitumoral de compuestos químicos en modelos de tumores humanos implantados en ratones
Exposición detallada de modos de realización / Ejemplos
La presente invención se explica a través de los siguientes ejemplos de realización:
Ejemplo 1 : Selección de los compuestos mediante modelación molecular in silico.
Mediante el uso del modelo computacional desarrollado a partir del acoplamiento molecular masivo se seleccionaron un grupo de compuestos basados en una alta energía de interacción calculada para el complejo ligando receptor como se muestra en Ia tabla siguiente. Esta energía aproximada se estima teniendo en cuenta un análisis exhaustivo de Ia conformación y de los componentes energéticos utilizando un programa computacional desarrollado en nuestro laboratorio. Tabla 1: Energías de interacción calculadas para el complejo ligando-receptor
Figure imgf000017_0001
Ejemplo 2: Efecto de los compuestos químicos descritos sobre Ia fosforilación de un sustrato típico de CK2.
Este ensayo consiste en una reacción de fosforilación in vitro donde se uso como sustrato Ia oncoproteína E7 del Virus Papiloma Humano tipo 16 (VPH-16) expresada en E. CoIi como proteína de fusión a Glutation S-Transferasa (GST). Posteriormente, Ia E7-GST se purificó por cromatografía de afinidad usando Glutation-Sefarosa (Pharmacia). Antes de Ia reacción enzimática, Ia E7-GST fue preincubada con diferentes concentraciones de los compuestos químicos mencionados en Ia invención durante una hora a 370C. La mezcla de reacción se realiza en 50 μl de buffer Tris:HCL 25 mM pH 7.5, 1 μCi de 32P- γATP, 100 μM ATP, 40 μl de Ia resina que contiene E7-GST, 0.2 M NaCI , 10 mM MgCI y 1 unidad de Ia enzima CK2 (Promega). La reacción se incuba a 370C durante 40 minutos. Seguidamente se realizan tres lavados de Ia resina con 0.5 mi del buffer de reacción y finalmente el nivel de fosforilación de Ia E7-GST es analizado en una electroforesis PAGE al 10%. La visualización de Ia proteína fosforilada se realizó mediante el revelado de placas de rayos X previamente expuestas con el gel seco. La cuantificación de Ia fosforilación de E7 se realizó mediante análisis de densitometría de las respectivas placas. Los valores de CI50 se estimaron a partir de las respectivas curvas dosis-efecto. La CI50 representa Ia concentración que inhibe el 50% de Ia actividad enzimática. Paralelamente se incluyó como control de comparación en el ensayo el péptido cíclico P15 reportado como inhibidor del sitio de fosforilación de los sustratos de CK2. Los resultados observados en Ia Tabla 2 indican que los diferentes compuestos químicos descritos en esta invención son inhibidores efectivos de un sitio de fosforilación típico de Ia CK2 según los valores de CI50 observados. Resulta interesante el hecho de que las moléculas químicas descritas en Ia invención muestran mayor capacidad inhibitoria respecto al péptido cíclico reportado previamente como inhibidor del sitio de fosforilación de CK2 que solamente ejerce su efecto inhibitorio en el rango micromolar. Tabla 2: Efecto inhibitorio de Ia fosforilación de un sustrato típico de CK2
Figure imgf000018_0001
Figure imgf000019_0001
Ejemplo 3: Efecto de los compuestos químicos descritos sobre el sitio consenso de fosforilación de Ia CK2.
Este ensayo consiste en una reacción de fosforilación in vito donde se usó como substrato Ia secuencia RRREEETEEE que representa el dominio consenso optimizado para Ia fosforilación por CK2. Previo a Ia reacción de fosforilación, el péptido sustrato se incubo durante una hora a 370C con los diferentes compuestos químicos descritos en Ia invención. Seguidamente, Ia mezcla de reacción se realizó en 50 μl de buffer Tris: HCL 25 mM pH 7.5, 1 μCi de 32P- γATP, 100 μM ATP, 2 mg/ml del péptido substrato, 0.2 M NaCI, 10 mM MgCI y 1 unidad de Ia enzima CK2 (Promega). La reacción se incubó a 370C durante 10 minutos. Seguidamente se aplicaron 5 μl de Ia reacción en papel de filtro Whatmann PE-81 y se realizaron cuatro lavados con 10 mM de H3PO4 Finalmente se midió Ia radiactividad asociada al papel de filtro y Ia cantidad de cpm por muestra refleja directamente Ia actividad enzimática de CK2. Paralelamente se incluyó como control de comparación en el ensayo el péptido cíclico P15 reportado como inhibidor del sitio de fosforilación de los sustratos de CK2. Los valores de CI50 que corresponden al efecto inhibitorio fueron estimados de las respectivas curvas dosis-efecto. La CI50 representa Ia concentración que inhibe el 50% de Ia actividad enzimática. Los resultados de este ejemplo plasmados en Ia Tabla 3, demostraron que los compuestos químicos mencionados en esta invención inhiben eficientemente Ia fosforilación del sustrato de CK2 in vitro según los valores de CI50 observados. Además, estos resultados indicaron una mayor eficacia inhibitoria de las moléculas químicas reportadas en Ia invención respecto al péptido cíclico previamente reportado como inhibidor del sitio de fosforilación de CK2. Tabla 3: Efecto de los compuestos químicos descritos sobre el sitio consenso de fosforilación de la CK2
Figure imgf000020_0001
Ejemplo 4: Efecto de los compuestos químicos de Ia presente invención sobre células tumorales humanas.
Para este ensayo, las células H-125 procedentes de un Carcinoma de Pulmón humano a Células No Pequeñas (NSCLC) se sembraron en placas de 96 pocilios (Costar) a una densidad de 2x104 células/ml en medio Dulbecco (DMEM) (Gibco) suplementado con Suero Fetal Bovino (Gibco). Al cabo de 24 horas, los compuestos químicos descritos en Ia presente invención se adicionaron al medio de cultivo en un rango de dosis comprendido entre 0.5 y 100 nM. La incubación fue realizada por espacio de 72 horas a 370C en presencia de CO2 al 5% y al término de Ia misma se adicionaron 20 μl de una solución de MTS 1.90 mg/ml. Las placas se mantuvieron 1 hora adicional en las mismas condiciones de incubación y finalmente se realizó Ia lectura de Ia absorbancia a 492 nm. Los resultados son mostrados como porciento de crecimiento de los controles sin compuestos químicos y los valores de IC50 fueron calculados a partir de las respectivas curvas de dosis-respuesta (Tabla 4). Los resultados obtenidos en este ensayo demuestran que los compuestos químicos de Ia presente invención tienen efecto citotóxico sobre células tumorales en cultivos in vitro. Además, se demuestra Ia superioridad de tales compuestos en cuanto a Ia eficacia citotóxica respecto al péptido cíclico P15 previamente descrito como inhibidor del sitio fosforilable de los sustratos de CK2. Tabla 4: Efecto de los compuestos químicos sobre células tumorales humanas
Figure imgf000021_0001
Ejemplo 5: Efecto antitumoral de los compuestos químicos de Ia invención en modelos de tumores humanos implantados en ratones atímicos. En estos ensayos se utilizaron ratones desnudos BaIbC de sexo femenino entre 6 y 8 semanas de nacidos. Para Ia implantación del tumor en este modelo se inocularon 5 000 000 de células H-125 resuspendidas en 250 μl de PBS en Ia región dorsal de los animales. Una vez que los tumores fueron palpables con un volumen alrededor de 50 mm3, se realizó Ia administración directa de 200 μg de los compuestos C32425, C33426 y C33427 de manera consecutiva durante 5 días. Como se puede observar en Ia Figura 1 , Ia administración de los compuestos químicos es capaz de producir una respuesta antitumoral significativa. Estos resultados evidencian Ia eficacia antitumoral de moléculas químicas inhibidoras del sitio de fosforilación de Ia CK2 en un modelo relevante de Ia oncología experimental.

Claims

REIVINDICACIONES
1) Compuestos químicos los cuales bloquean Ia fosforilación por Caseína Kinasa 2 (CK2) y con acción antineoplásíca, caracterizados porque cumple con uno o varios de los siguientes requerimientos: a. Se unen al dominio de fosforilación o a su entorno en el sustrato de Ia CK2, bloqueando directa o indirectamente Ia unión de Ia enzima al sustrato. b. Impiden directa o indirectamente Ia transferencia del grupo fosfato a Ia serina fosfoaceptora. c. Su unión a Ia proteína sustrato de Ia CK2, genera un cambio conformacional en el dominio de fosforilación, su entorno o ambos, de forma directa o indirecta, acorde a Io descrito en a y b.
2) Compuestos químicos y sus variantes homologas, según Ia reivindicación 1 , donde Ia estructura química está definida por Ia ocurrencia, en cualquier parte de
Ia molécula, de manera consecutiva de los siguientes elementos enlazados entre sí y con las características de hibridación señaladas y son seleccionados de al menos uno de los siguientes grupos:
I. N-[C(sp2)]1l2,3-N II. N-[C(sp2)]1>2-[C(sp3)]1,2,3-N
III. N-[C(SpS)]L213-N
IV. N-C(sp2)-[C(sp3)]i ,2-C(sp2)-N
V. N-C(sp3)-[C(sp2)]i,2-C(sp3)-N
3) Composición farmacéutica para el tratamiento de enfermedades donde Ia CK2 posea un papel patológico y otras relacionadas con procesos neoplásicos, que comprende uno o más de los compuestos químicos o sus sales farmacéuticamente aceptables, como se definen en cualquiera de las reivindicaciones 1 y 2 y excipientes o vehículos farmacéuticamente aceptables.
4) Uso de los compuestos químicos como se definen en cualquiera de las reivindicaciones 1 y 2, para Ia manufactura de medicamentos para Ia inhibición de Ia proliferación de células tumorales ¡n vitro, ¡n vivo o en dispositivos asociados al cuerpo y para el tratamiento del cáncer en seres vivos y otras enfermedades donde Ia CK2 posea un papel patológico.
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RU2007146169A (ru) 2009-06-20
MX2007014216A (es) 2008-02-07
AU2006246204A1 (en) 2006-11-16
AU2006246204B2 (en) 2012-04-19
PT1892245E (pt) 2015-11-12
PT2474528E (pt) 2014-10-28
US20090215730A1 (en) 2009-08-27
US8748411B2 (en) 2014-06-10
MY140530A (en) 2009-12-31

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