WO2013042065A2 - Inhibiteurs de protéines inactivatrices de ribosome de type ii - Google Patents

Inhibiteurs de protéines inactivatrices de ribosome de type ii Download PDF

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Publication number
WO2013042065A2
WO2013042065A2 PCT/IB2012/054999 IB2012054999W WO2013042065A2 WO 2013042065 A2 WO2013042065 A2 WO 2013042065A2 IB 2012054999 W IB2012054999 W IB 2012054999W WO 2013042065 A2 WO2013042065 A2 WO 2013042065A2
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compound
ricin
shiga
saporin
abrin
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WO2013042065A3 (fr
WO2013042065A4 (fr
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Kevin Jonathan NAIDOO
Ranga Srinath JAYAKODY
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University of Cape Town
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University of Cape Town
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • This invention relates to compounds which are capable of inhibiting ribosome inactivating protein (RIP) type II lectins and to the use of these compounds in pharmaceutical compositions for treating or preventing diseases or infections.
  • RIP ribosome inactivating protein
  • Ribosome inactivating proteins are protein synthesis inhibitors that act at the ribosome.
  • Members of the family include Shiga and Shiga-like toxins, trichosanthin, luffin, saporin, ricin, agglutinin and abrin.
  • Ricin from the castor oil plant Ricinus communis, is a very toxic type II ribosome inactivating protein (RIP). A dose as small as 1 .76 mg can kill an adult.
  • RIP ribosome inactivating protein
  • Ricin has been investigated for its military potential by at least the United States, Canada and the Soviet Union. The toxin has been involved in a number of incidents, including the high-profile "umbrella-tip" assassination of Georgi Markov in 1978. More recently, there have been press reports of extremist groups and individuals planning to use ricin in terrorist attacks. Ricin also has the potential to be a therapeutic protein or immunotoxin for use in, for example, the treatment of autoimmune diseases, psoriasis, cancer, HIV infection or AIDS. However, due to non-specific cytotoxicity and immunogenicity which result when ricin is administered, repeat dosing is prevented and the therapeutic use of ricin has not yet been approved.
  • Abrin is a toxalbumin found in the seeds of a plant called the lucky bean (or the rosary pea or jequirity pea). Although it is far more deadly than ricin, it has some potential uses, such as in treatment to kill cancer cells.
  • Another RIP is Shiga.
  • the most common sources for Shiga toxin are the bacteria S. dysenteriae and the Shigatoxigenic group of Escherichia coli (STEC), which includes serotypes 0157:1-17, 0104:1-14, and other enterohemorrhagic E. coli (EHEC). It is estimated that at least 90 people die each year from coming into contact with E. coli that make Shiga or Shiga-like toxins, and thousands more are hospitalized.
  • Saporin from the seeds of Saponaria officinalis (soapwort), is another RIP. It has been used in research as an immunotoxin for leukaemia and lymphoma and to target and eliminate neuronal populations. To date no effective antidote is known for ricin or its related family members. There is therefore a need for a compound or composition which can inhibit ricin or its related toxins, such as Shiga, saporin and abrin.
  • a compound which is a ricin, abrin, Shiga or saporin inhibitor, wherein the compound has a bipartite configuration comprising an aromatic heterocyclic structure that resembles an adenine moiety in size and shape connected at the C8 position to an aromatic or non-aromatic cyclic ring structure that resembles a ribose moiety in size and shape.
  • the compound may be of formula (I):
  • Y -S-, -0-, -CH 2 -, -NH-, or -PH-;
  • W a 5- or 6-membered aromatic or non-aromatic cyclic ring selected from any one of formulae (II) to (XX), or a derivative thereof:
  • the compound of formula (I) may be selected from compounds of the formulae (XXI), (XXII), (XXIII) or (XXIV):
  • ⁇ is selected from any one of -(S)-, -(O)-, -(CH 2 )-, -(NH)-, or -(PH); and ⁇ is selected from any one of -(S)-, -(O)-, -(CH 2 )-, -(NH)-, or -(PH), or any isomers, tautomers, pharmaceutically acceptable salts, esters or prodrugs thereof.
  • the compound may be for use in controlling non-specific cytotoxicity due to ricin, abrin, Shiga or saporin, and more particularly for treating diseases or conditions such as psoriasis, autoimmune diseases or cancer, HIV infection or AIDS.
  • diseases or conditions such as psoriasis, autoimmune diseases or cancer, HIV infection or AIDS.
  • a compound substantially as described above in a method of manufacturing a medicament for use in a method of for use in a method of inhibiting ricin, abrin, Shiga or saporin and/or of treating non-specific cytotoxicity, and in particular of treating psoriasis, autoimmune diseases or cancer, HIV infection and AIDS.
  • a pharmaceutical composition comprising a compound substantially as described above and a pharmaceutically acceptable excipient or additive.
  • a method for identifying a compound which is effective for inhibiting ricin, abrin, Shiga or saporin comprising the step of identifying a test compound which:
  • i) has an adenine resembling moiety and a ribose resembling moiety which are connected to each other via the C8 of the adenine resembling moiety;
  • a method of inhibiting ricin, abrin, Shiga or saporin or of controlling non-specific cytotoxicity due to ricin, abrin, Shiga or saporin when using it as a therapeutic agent, such as for treating psoriasis, autoimmune diseases, cancer, HIV infection or AIDS comprising the step of administering a therapeutically effective amount of a compound substantially as described above along with the ricin, abrin, Shiga or saporin to a subject in need of such treatment.
  • Figure 1 shows binding of a natural substrate (a 12-mer RNA) loop to ricin.
  • the ricin backbone is shown in blue;
  • the RNA loop is shown in green and the target adenine is highlighted in a liquorish representation;
  • Figure 2 shows the ricin transition state ESP
  • Figure 3 shows transition state analogues identified herein as potential new inhibitors of ricin
  • Figure 4 shows binding of the newly identified ricin inhibitors to RTA;
  • Figure 5 shows a comparison of binding sites of abrin, Shiga, saporin and ricin;
  • Figure 6 shows docking results of the newly identified inhibitors to abrin
  • Figure 7 shows docking results of the newly identified inhibitors to Shiga.
  • Figure 8 shows docking results of the newly identified inhibitors to saporin.
  • Inhibitors of type II ribosome inactivating proteins such as ricin, abrin, Shiga and saporin are described herein.
  • the identified inhibitors can be used as antidotes to these toxins or to facilitate immunotoxin treatment by controlling non-specific cytotoxicity. More specifically, it is anticipated that the inhibitors could be used for the treatment or prevention of diseases or conditions such as psoriasis, autoimmune diseases, cancers, HIV infection or AIDS 8 .
  • Inhibitors have been identified which have a bipartite configuration comprising an aromatic heterocyclic structure resembling an adenine moiety in size and shape connected at the C8 position to an aromatic or non-aromatic cyclic ring structure resembling a ribose moiety in size and shape.
  • Adenine and ribose moieties will be well-known to those skilled in the art of the present invention. Structures resembling a ribose moiety are 5- or 6-membered cyclic rings, with the ring atoms generally being selected from C, O, N or S and the side groups or atoms attached to the ring generally being OH or H.
  • inhibitors are compounds of formula (I):
  • X -S-, -0-, -CH 2 -, -NH-, -PH-, -0-Y-, -CH 2 -Y-, -NH-Y-, -PH-Y, or -S-Y;
  • Y -S-, -0-, -CH 2 -, -NH-, or -PH-;
  • W a 5- or 6-membered aromatic or non-aromatic cyclic ring selected from any one of formulae (II) to (XX) or a derivative thereof:
  • Derivates could be derived by replacing one or more ring atoms and/or by replacing one or more ring hydrogens with any atom or group of atoms.
  • suitable compounds of formula (I) include compounds of formulae (V), (VI),
  • ⁇ is selected from any one of -(S)-, -(O)-, -(CH 2 )-, -(NH)-, and -(PH)-; and ⁇ is selected from any one of -(S)-, -(O)-, -(CH 2 )-, -(NH)-, and -(PH)-, or any isomers, tautomers, pharmaceutically acceptable salts, esters or prodrugs thereof.
  • RIPs are structurally related and the RIP active site is preserved.
  • Ricin is classified as a type II RIP.
  • type I RIPs consist of a single enzymatic protein chain
  • type II RIPs are heterodimeric glycoproteins.
  • Type II RIPs consist of an A chain that is functionally equivalent to a type I RIP and is catalytically active, and which is covalently connected by a single disulfide bond to a B chain that is catalytically inactive, but serves to mediate entry of the A-B protein complex into the cytosol.
  • Both type I and type II RIPs are functionally active against ribosomes in vitro, but only type II RIPs display cytoxicity due to the lectin properties of the B chain. In order to display its ribosome inactivating function, the ricin disulfide bond must be reductively cleaved.
  • the tertiary structure of ricin is a globular, glycosylated heterodimer of approximately 60-65 kDA 7 .
  • Ricin toxin A chain and ricin toxin B chain are of similar molecular weight, approximately 32 kDA and 34 kDA respectively.
  • Ricin A Chain is an N-glycoside hydrolase composed of 267 amino acids. 1 It has three structural domains with approximately 50% of the polypeptide arranged into alpha-helices and beta-sheets. The three domains form a pronounced cleft that is the active site of RTA.
  • Ricin B Chain is a lectin composed of 262 amino acids that is able to bind terminal galactose residues on cell surfaces 2 6 .
  • RTB form a bilobal, barbell-like structure lacking alpha-helices or beta-sheets where individual lobes contain three subdomains. At least one of these three subdomains in each homologous lobe possesses a sugar- binding pocket that gives RTB its functional character.
  • Ricin inactivates 60S ribosomal subunits by an N-glycosidic cleavage which releases the adenine base at position 4324 (A4324) from the sugar-phosphate backbone of the 28S rRNA, but leaves the phosphodiester backbone of the RNA intact.
  • A4324 is contained in a highly conserved sequence of 12 nucleotides universally found in eukaryotic ribosomes. The sequence, 5'-AGUACGAGAGGA-3', termed the sarcin-ricin loop, is important in binding elongation factors during protein synthesis. The depurination event rapidly and completely inactivates the ribosome, resulting in toxicity from inhibited protein synthesis.
  • a single RTA molecule in the cytosol is capable of depurinating approximately 1500 ribosomes per minute. Not only is the structure for all RIPs similar, but the RIP active site is also preserved and the RIPs catalyse the same depurination reaction. Specifically, abrin, Shiga, saporin and ricin have the same set of catalytic residues. The corresponding residue numbers for the catalytic sets of abrin, Shiga, saporin and ricin are shown in Table 1 . Table 1 : Common catalytic residues of RIP proteins
  • the reaction simulation was carried out using the hybrid Quantum Mechanical-Molecular Mechanical (QM/MM) approach with an in-house computer software program named Free Energys from Adaptive Reaction Coordinate Forces (FEARCF). 3 ' 4 ' 9 10
  • QM/MM Quantum Mechanical-Molecular Mechanical
  • FEARCF Adaptive Reaction Coordinate Forces
  • the starting structure for ricin was obtained from the PDB file 1 FMP, wherein ricin is bound to formycin monophosphate (FMP), a substrate analogue for ricin.
  • the initial substrate structure was obtained from high resolution NMR studies of the ricin-saricin target loop (PDB ID : 1 ZIG).
  • the parent RNA loop was reduced to a total of 12 nucleic acid bases including the ricin target GAGA tetra loop. It was found that the model must have at least 12 bases to maintain the integrity of the RNA loop during the simulations.
  • the target adenine in this loop was manually flipped (as proposed by various base flipping mechanisms) to facilitate its docking to the RTA binding site.
  • the substrate loop was manually docked to the RTA binding site as guided by the binding of FMP.
  • a snap shot of this system was taken as the starting structure for a QM/MM dynamics simulation.
  • reaction simulations were carried out as mentioned earlier.
  • the length of the C1 '-N9 bond (susceptible glycosidic bond) and the length of the forming bond between the incoming OH " nucleophile and C1 ' were used as the reaction coordinates in the reaction simulations.
  • the starting structure of the substrate: ricin complex is shown in Figure 1 .
  • the mechanism proposed in this study for the ricin-catalysed RNA depurination reaction is shown below.
  • the major steps in the reaction mechanism are: (i) reversible cleavage of the C1 '-N9 bond, (ii) activation of the catalytic water molecule and generation of the OH " nucleophile, (iii) formation of the transition state (TS), (iv) permanent departure the adenine base, attack by the OH " at C1 ' and formation of the final products.
  • the molecular core is bipartite and has an adenine resembling moiety and a ribose resembling moiety. It was found that any linkage via the N9 position of the adenine resembling moiety to the sugar resembling moiety jeopardizes the preferred (matching to the transition state) ESP of the new molecule. Therefore, in this molecular core, the connection between the adenine resembling moiety and the sugar resembling moiety was designed to be via the C8 of the adenine resembling moiety, so as to preserve the desired ESP.
  • the molecular core described herein is far less reactive than previously suggested structures as it does not have any kind of linkage between C1 ' and N9. This C8 linkage is not found in any of the previously proposed bipartite ricin inhibitors.
  • FIG 4 depicts the binding of the new inhibitors to RTA.
  • Each 2D ligand interaction diagram depicts each ligand in the RTA binding site. Binding of the adenine moiety of these ligands is identical to the binding of the leaving (adenine) group in the transition state structure to RTA. Depending on its structure, each ligand shows a unique binding pattern to RTA for its ribose resembling moiety.
  • the X-ray crystal structures of other RIPs (abrin, Shiga and saporin) were obtained from the protein data bank and their binding sites were compared with that of ricin (Figure 5).
  • the ricin inhibitors identified above were docked to abrin, Shiga and saporin and the pose that was most similar to the pose of the transition state in the ricin binding site was selected for each inhibitor. In some cases, no similar pose was obtained. However, a person skilled in the art will realise that this does not necessarily mean that a ricin-TS-like-pose is not possible. It might be the case that binding sites of these enzymes were "pre-defined" for another inhibitor or for the apo enzyme, but not for the transition state.
  • the initial docking results are presented in Figures 6 to 8. These promising initial results show the potency of the compounds identified herein as new inhibitors against abrin, saporin and Shiga toxins.
  • the methodology described herein differs from conventional high throughput screening (HTS), where millions of compounds are analyzed to identify potential leads.
  • HTS high throughput screening
  • This is usually performed using a pharmacophore that is designed based on the structure of the active site (structure-based-design).
  • the pharmacophore was designed based on a molecular core that mimics the transition state of the reaction, and a combined- screening (pharmacophore and ESP) strategy was used to search for and/or design transition state analogue inhibitors which could be potential ricin, abrin, Shiga or saporin inhibitors.
  • the present strategy also requires the inhibitors to have the 8 th position of the base moiety connected to the sugar-like moiety, whereas previously proposed inhibitors use the 9 th position of the base for this purpose.

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Abstract

L'invention concerne des composés qui sont inhibiteurs de ricine, d'abrine, de Shiga ou de saporine et qui ont une configuration bipartite comprenant une structure hétérocyclique aromatique ressemblant à une fraction adénine en dimension et en forme, connectée à la position C8 d'une structure de cycle cyclique aromatique ou non aromatique ressemblant à une fraction ribose en dimension et en forme. Plus particulièrement, les inhibiteurs ont la formule (I) : (I) où X = -S-, -O-, -CH 2 -, -NH-, -PH-, -O-Y-, -CH 2 -Y-, -NH-Y-, -PH-Y ou -S-Y ; Y = -S-, -O-, -CH 2 -, -NH- ou -PH- ; et W = un cycle cyclique aromatique ou non aromatique à 5 ou 6 chaînons. L'invention concerne également des utilisations de ces composés dans la fabrication d'un médicament et dans le traitement d'un sujet, ainsi qu'un procédé d'identification d'inhibiteurs appropriés.
PCT/IB2012/054999 2011-09-20 2012-09-20 Inhibiteurs de protéines inactivatrices de ribosome de type ii Ceased WO2013042065A2 (fr)

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ZA201106840 2011-09-20
ZA2011/06840 2011-09-20

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WO2013042065A2 true WO2013042065A2 (fr) 2013-03-28
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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6562969B1 (en) * 1996-12-24 2003-05-13 Research Development Foundation Ricin inhibitors and methods for use thereof
AU6237798A (en) * 1996-12-24 1998-07-17 Research Development Foundation Ricin inhibitors and methods for use thereof
CA2538169A1 (fr) * 2003-09-09 2005-03-17 Albert Einstein College Of Medicine Of Yeshiva University Inhibiteurs d'analogues d'etat de transition de chaine a de toxine de ricin
US7834181B2 (en) * 2005-02-01 2010-11-16 Slaon-Kettering Institute For Cancer Research Small-molecule Hsp90 inhibitors

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
APLIN PJ; ELISEO T., MED. J. AUST., vol. 167, no. 5, 1997, pages 260 - 261
BARNETT, C. B.; NAIDOO, K., J. MOL. PHYS., vol. 107, 2009, pages 1243 - 1250
CUI, Q.; ELSTNER, M.; KAXIRAS, E.; FRAUENHEIM, T.; KARPLUS, M., J. PHYS. CHEM. B., vol. 105, 2001, pages 569 - 585
FODSTAD, 0.; OLSNES, S.; PIHL, A., CANCER RES., vol. 37, 1977, pages 4559 - 4567
NAIDOO, K. J., PHYSICAL CHEMISTRY CHEMICAL PHYSICS, vol. 14, 2012, pages 9026 - 9036
NAIDOO, K. J., SCIENCE CHINA CHEMISTRY, vol. 54, 2011, pages 1962 - 1973
OLSNES, S., PIHL, A. BIOCHEMISTRY, vol. 12, 1973, pages 3121 - 3126
OLSNES, S.; REFSNES, K.; PIHL, A., NATURE, vol. 249, 1974, pages 627 - 631
STRÜMPFER, J.; NAIDOO, K. J., J. COMP. CHEM., vol. 31, 2010, pages 308 - 316
WALES R.; RICHARDSON, P. T.; ROBERS, L. M.; WOODLAND, H. R. ET AL., J BIOL CHEM., vol. 266, 1991, pages 19172 - 79

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WO2013042065A4 (fr) 2013-08-15

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