WO2009135000A2 - Inhibition de la protéine tyrosine phosphatase shp2/ptpn11 par nsc-117199 et analogues - Google Patents

Inhibition de la protéine tyrosine phosphatase shp2/ptpn11 par nsc-117199 et analogues Download PDF

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WO2009135000A2
WO2009135000A2 PCT/US2009/042305 US2009042305W WO2009135000A2 WO 2009135000 A2 WO2009135000 A2 WO 2009135000A2 US 2009042305 W US2009042305 W US 2009042305W WO 2009135000 A2 WO2009135000 A2 WO 2009135000A2
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alkyl
group
coo
shp2
phenyl
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WO2009135000A3 (fr
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Jie Wu
Nicholas J. Lawrence
Said M. Sebti
Harshani R. Lawrence
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University of South Florida
H Lee Moffitt Cancer Center and Research Institute Inc
University of South Florida St Petersburg
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University of South Florida
H Lee Moffitt Cancer Center and Research Institute Inc
University of South Florida St Petersburg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to cancer therapy. More specifically, this invention relates to compounds useful in inhibiting Shp2/PTPN1 1 protein tyrosine phosphatase activity.
  • protein tyrosine kinases and protein tyrosine phosphatases (PTP).
  • PTP protein tyrosine phosphatases
  • Many protein tyrosine kinases such as Bcr-Abl, c-kit, ErbB, and VEGFR are validated drug targets for cancer therapy (Bridges AJ. Chem. Rev. 2001, 101, 2541 -2571 ), however little work has been performed on development of protein tyrosine phosphatase inhibitors as an alternative strategy to modulate key target protein phosphorylation states (Bialy L and Waldmann H.
  • Shp2 encoded by the PTPN1 1 gene, is a non-receptor PTP with two Src homology-2 (SH2) domains (N-SH2, C-SH2), (Alonso A, et al.
  • Shp2 is basally inactive due to auto-inhibition by its N-SH2 domain (Hot P, et al. Cell 1998, 92(4) :441 -450). In growth factor- and cytokine-stimulated cells, Shp2 binds to tyrosine- phosphorylated docking proteins through its SH2 domains, resulting in its activation (Cunnick JM, et al. J Biol. Chem. 2001 , 276(26) :24380-24387). Shp1 is mostly expressed in hematopoietic and epithelial cells and functions as a negative regulator of signaling pathways in lymphocytes. (Neel, B., Tonks, N., Curr. Opin. Cell Biol.
  • Shp1 shows a similar arrangement of tandem SH2 domains that adopt a conformation blocking the PTP catalytic site.
  • Shp2 has been shown to bind Gab1 (or Gab2) in cells stimulated with EGF, HGF, or interleukin-6 (Cunnick JM, et al. J Biol. Chem. 2001 , 276(26) :24380-24387; Gu H and Neel BG. Trends Cell. Biol.
  • Shp2 growth factor-activation of Shp2 has been elucidated, the mechanisms by which Shp2 produces downstream signals, like activation of Ras-Erk1/2 MAP kinase pathway, are less clear (Mohi MG, et al. Cancer Cell 2005, 7(2):179-191 ).
  • Gain-of-function Shp2 mutants are found in childhood hematological malignancies such as juvenile myelomonocytic leukemia (JMML), some cases of solid tumors, and are associated with -50% cases of Noonan syndrome. (Bentires-Alj, M.; et al. Nat. Med. 2006, 12, 283-285) (Bentires-Alj M, et al. Cancer Res. 2004, 64(24) :8816-8820; Tartaglia M and GeIb BD. Eur. J. Med. Genet. 2005, 4S(2):81 -96).
  • JMML juvenile myelomonocytic leukemia
  • JMML is a progressive myelodysplastic/myeloproliferative disorder characterized by overproduction of tissue-infiltrating myeloid cells. Somatic mutations in PTPN1 1 account for about 35% of JMML patients, (Kratz CP, et al. Blood 2005, 706(6) :2183-2185) and recent reports indicated JMML-associated Shp2 mutants can transform murine bone marrow and fetal liver cells (Chan RJ, et al. Blood 2005, 705(9):3737- 3742; Mohi MG, et al. Cancer Cell 2005, 7(2):179-191 ; Schubbert S, et al. Blood 2005, 706(1 ):31 1 -317).
  • Noonan syndrome is a developmental disorder characterized by facial anomalies, short stature, heart disease, skeletal defects, and hematological disorders (Tartaglia M and GeIb BD. Eur. J. Med. Genet. 2005, 4S(2):81 -96), with about 50% of cases caused by germline PTPN1 1 mutations. All Shp2 mutants found in Noonan syndrome and JMML are gain-of-function mutations, mostly resulting from weaker autoinhibition of the N- SH2 domain (Fragale A, et al. Hum. Mutat. 2004, 23(3):267-277). It has also been reported that Shp2 is a key mediator of the oncogenic CagA protein of Helicobacter pylori, which causes gastric cancer. (Higashi, H.; et al. Science 2002, 295, 683-6; Meyer-ter-Vehn, T.; et al. J. Biol. Chem. 2000, 275, 16064-72).
  • PTP inhibitor development is an emerging area in the field of drug development (Bialy L and Waldmann H. Angew Chem. Int. Ed. Engl. 2005, 44(25):3814-3839).
  • Several compounds have been reported to non-selectively inhibit Shp2, with most efforts of PTP inhibitor discovery and design focused on PTP1 B and Cdc25 inhibitors (Lazo JS, et al. MoI.
  • Shp2-specific inhibitor that does not cross-inhibit Shp1 is important for development of effective treatment modalities.
  • Developing a Shp2-specific inhibitor is complicated by the similarity between Shp1 and Shp2, which share 60% overall sequence identity and approximately 75% similarity in their PTP domains.
  • Shp1 and Shp2 catalytic domains have different substrate specificity (Tenev, T., et al., J. Biol. Chem. 1997,
  • the PTP catalytic cleft consists of a base and four sides in the 3D structures (Hof P, et al. Ce// 1998, 92(4):441 -450; Yang J, et al. J. Biol. Chem. 2003,
  • the present invention provides compounds and associated methods for inhibiting a protein tyrosine phosphatase.
  • Experimental and virtual screenings of the NCI Diversity Set chemical library identified NSC-87877 and NSC-1 17199 as Shp2 PTP inhibitors.
  • NSC- 117199 exhibited some selectivity between Shp1 and Shp2.
  • NSC-1 17199 analogs were designed to enhance protein tyrosine phosphatase inhibition and provide specificity between Shp1 and Shp2.
  • the indole R 1 is a functional group, includes SO 3 H, CO 2 H, CONHCH 2 (4-CIC 6 H 4 ), SO 2 NH 1 Pr, SO 2 NH 2 , SO 2 NHCH 2 (2-CIC 6 H 4 ), SO 2 NHCH 2 (3-CIC 6 H 4 ), SO 2 NHCH 2 (4-CIC 6 H 4 ), SO 2 NHCH 2 (4-MeC 6 H 4 ), SO 2 NHCH 2 (3-CF 3 -4-CI-C 6 H 4 ), SO 2 NHCH 2 (4-FC 6 H 4 ), SO 2 NHCH 2 (3- 01-4-F-C 6 H 4 ), (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , SO 2 NH(CH 2 ) 2 (2-CI-4-CIC 6 H 4 ), SO 2 N-R8, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight-chained alkyl, branche
  • the phenylhydrazone moieties R 2 through R 6 are independently hydrogen, NO 2 , COO " , COO 2 H, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight-chained alkyl, branched alkyl, cyclic alkyl, SO 3 H, CO 2 NH 2 , SO 2 NH 2 , PO 3 H, CF 2 PO 3 H, (CH 2 ) n CO 2 H, (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , (CH 2 ) n SO 2 NH 2 , (CH 2 ) n PO 3 H, O(CH 2 ) n CO 2 H, O(CH 2 ) n SO 3 H, O(CH 2 ) n CO 2 NH 2 , O(CH 2 ) n SO 2 NH 2 , O(CH 2 ) n PO 3 H, NH(CH 2 ) n CO 2 H, NH
  • the R 7 group attached to the indole nitrogen may be either is hydrogen or methyl.
  • the R 1 group at the 5-position of the oxindole moiety is either a carboxylic acid, a sulfonamide, and a carboxylamide, bis- carboxylic acid, bis-carboxylic acid derivative, or p-halosulfonamide.
  • the p- halosulfonamide may be chloridesulfonamide.
  • specific embodiments of the compound possess a polar group on the oxindole moiety and a carboxylate or carboxylic acid on the phenylhydrazone moiety.
  • the compound may comprise a z-configuration iastin hydrazone.
  • a compound is administered to the cell, such as by contacting the cell with an effective amount of a the compound having the formula
  • the compound may comprise indole R 1 is a functional group, including includes SO 3 H, CO 2 H, CONHCH 2 (4-CIC 6 H 4 ), SO 2 NH 1 Pr, SO 2 NH 2 , SO 2 NHCH 2 (2-CIC 6 H 4 ), SO 2 NHCH 2 (3-CIC 6 H 4 ), SO 2 NHCH 2 (4-CIC 6 H 4 ), SO 2 NHCH 2 (4-MeC 6 H 4 ), SO 2 NHCH 2 (3-CF 3 -4-CI-C 6 H 4 ), SO 2 NHCH 2 (4- FC 6 H 4 ), SO 2 NHCH 2 (3-CI-4-F-C 6 H 4 ), (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , SO 2 NH(CH 2 ) 2 (2-CI-4- CIC 6 H 4 ), SO 2 N-R8, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight- chained alky
  • the phenylhydrazone moieties R 2 through R 6 are independently hydrogen, NO 2 , COO " , COO 2 H, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight-chained alkyl, branched alkyl, cyclic alkyl, SO 3 H, CO 2 NH 2 , SO 2 NH 2 , PO 3 H, CF 2 PO 3 H, (CH 2 ) n CO 2 H, (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , (CH 2 ) n SO 2 NH 2 , (CH 2 ) n PO 3 H, O(CH 2 ) n CO 2 H, O(CH 2 ) n SO 3 H, O(CH 2 ) n CO 2 NH 2 , O(CH 2 ) n SO 2 NH 2 , O(CH 2 ) n PO 3 H, NH(CH 2 ) n CO 2 H, NH
  • the R 7 group attached to the indole nitrogen may be either is hydrogen or methyl.
  • the R 1 group at the 5-position of the oxindole moiety is either a carboxylic acid, a sulfonamide, and a carboxylamide, bis-carboxylic acid, bis-carboxylic acid derivative, or p- halosulfonamide.
  • the p-halosulfonamide may be chloridesulfonamide.
  • specific embodiments of the compound possess a polar group on the oxindole moiety and a carboxylate or carboxylic acid on the phenylhydrazone moiety.
  • the compound may comprise a z-configuration iastin hydrazone.
  • the protein tyrosine phosphatase inhibited by the method is a Shp2 protein tyrosine phosphatase. More specifically, the Shp protein tyrosine phosphatase is selectively inhibited.
  • a method of treating a disease in an animal is disclosed. A compound is administered to the cell, such as by contacting the cell with an effective amount of a the compound having the formula
  • the compound may comprise indole R 1 is a functional group, including includes SO 3 H, CO 2 H, CONHCH 2 (4-CIC 6 H 4 ), SO 2 NH 1 Pr, SO 2 NH 2 , SO 2 NHCH 2 (2-CIC 6 H 4 ), SO 2 NHCH 2 (3-CIC 6 H 4 ), SO 2 NHCH 2 (4-CIC 6 H 4 ), SO 2 NHCH 2 (4-MeC 6 H 4 ), SO 2 NHCH 2 (3-CF 3 -4-CI-C 6 H 4 ), SO 2 NHCH 2 (4- FC 6 H 4 ), SO 2 NHCH 2 (3-CI-4-F-C 6 H 4 ), (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , SO 2 NH(CH 2 ) 2 (2-CI-4- CIC 6 H 4 ), SO 2 N-R8, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight- chained alky
  • the phenylhydrazone moieties R 2 through R 6 are independently hydrogen, NO 2 , COO " , COO 2 H, phenyl, nitro, carboalkoxy, carboxyamide, benzylcarboxamide, straight-chained alkyl, branched alkyl, cyclic alkyl, SO 3 H, CO 2 NH 2 , SO 2 NH 2 , PO 3 H, CF 2 PO 3 H, (CH 2 ) n CO 2 H, (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 NH 2 , (CH 2 ) n SO 2 NH 2 , (CH 2 ) n PO 3 H, O(CH 2 ) n CO 2 H, O(CH 2 ) n SO 3 H, O(CH 2 ) n CO 2 NH 2 , O(CH 2 ) n SO 2 NH 2 , O(CH 2 ) n PO 3 H, NH(CH 2 ) n CO 2 H, NH
  • the R 7 group attached to the indole nitrogen may be either is hydrogen or methyl.
  • the R 1 group at the 5-position of the oxindole moiety is either a carboxylic acid, a sulfonamide, and a carboxylamide, bis-carboxylic acid, bis-carboxylic acid derivative, or p- halosulfonamide.
  • the p-halosulfonamide may be chloridesulfonamide.
  • specific embodiments of the compound possess a polar group on the oxindole moiety and a carboxylate or carboxylic acid on the phenylhydrazone moiety.
  • the compound may comprise a z-configuration iastin hydrazone.
  • the method may be used to treat a protein tyrosine phosphatase disease, including Noonan syndrome, juvenile myelomonocytic leukemia, Noonan-like disorder with multiple giant cell lesion syndrome, LEOPARD syndrome, acute lymphoblastic leukemia, acute myelogenous leukemia, H. pylori-associated gastritis, or gastric cancer.
  • the method may target a protein tyrosine phosphatase for inhibition.
  • the protein tyrosine phosphatase is a Shp2 protein tyrosine phosphatase.
  • Figure 1 illustrates the molecular model of NSC-87877 binding to the Shp2 PTP domain.
  • the hydrogen bonds formed between the NSC-87877 and the protein, via Arg-465, Lys-280 and Asn-281 are shown schematically but not to scale.
  • the hydrogen bonds are defined with a minimum donor angle of 90 ° and minimum acceptor angle of 60 ° and maximum length of 2.5 A
  • FIG. 2 depicts the inhibition of EGF-stimulated Shp2 activation by NSC-87877.
  • Figure 3 is a model depicting the overlay of NSC-117199 (dark-shaded chemical structure) and HL2-052-2 (light-shaded chemical structure) in the SH P2 active site.
  • Figure 4(a) and (b) are diagrammatic model of Shp2 ligand docking.
  • 4(a) models compound 5 and annotates some identified, important structural features for activity.
  • 4(b) models structure 6, representing the oxindole phamacophore for new inhibitor design.
  • Figure 5 is an illustration of reaction scheme 1. The following reagents and conditions were used: a) NBS, isopropanol:H 2 O (95:5), 0 0 C, 45 min; b) i: HCI (aq. 4M, 1 -3 ml_), ⁇ w, 150 0 C, 5 min, ii: HCI (aq.
  • Figure 6 is an illustration of reaction scheme 2.
  • the following reagents and conditions were used: a) NBS, isopropanol:H 2 O (95:5), 0 0 C, 45 min; b) i: HCI (aq. 4M, 1 -3 ml_), ⁇ w, 150 0 C, 5 min, ii: HCI (aq.
  • FIG. 7 is a table of Shp2 active compounds from the isatin library. a Values are means and standard deviations of at least 4 experiments, each performed in duplicate.
  • Figures 8(a) and (b) are model depicting the overlay of compound 5 and compound 14a.
  • 8(a) models the overlay of 5 (NSC-1 17199) (black) and 14a (gray) docked in the Shp2 PTP active site.
  • 8(b) models compound 14a docked to Shp1 PTP active site.
  • Shp2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN1 1 gene. It is involved in growth factor-induced activation of mitogen-activated protein (MAP) kinases Erk1 and Erk2 (Erk1/2) and has been implicated in the pathogenicity of the oncogenic bacterium Helicobacter pylori (H. pylon). Moreover, gain-of-function Shp2 mutations have been found in childhood leukemias and Noonan syndrome. Thus, small molecule Shp2 PTP inhibitors are much needed reagents for evaluation of Shp2 as a therapeutic target and for chemical biology studies of Shp2 function.
  • MAP mitogen-activated protein
  • NSC-87877 was identified as a potent Shp2 PTP inhibitor.
  • Site-directed mutagenesis and molecular modeling studies suggested that NSC-87877 binds to the catalytic cleft of Shp2 PTP.
  • NSC-87877 cross-inhibited Shp1 in vitro, but it was selective for Shp2 over other PTPs (PTP1 B, HePTP, DEP1 , CD45, and LAR).
  • PTP1 B HePTP
  • DEP1 , CD45, and LAR other PTPs
  • NSC-87877 inhibited EGF-induced activation of Shp2 PTP, Ras, and Erk1/2 in cell cultures but did not block EGF-induced Gab1 tyrosine phosphorylation or Gab1 -Shp2 association.
  • NSC-87877 inhibited Erk1/2 activation by a Gab1 -Shp2 chimera but did not affect the Shp2-independent Erk1/2 activation by phorbol 12-myristate 13-acetate (PMA).
  • PMA phorbol 12-myristate 13-acetate
  • administration means introducing the compound or a prodrug of the compound into the system of the animal.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • a "safe and effective amount” refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • a “pharmaceutically acceptable carrier” is a carrier, such as a solvent, suspending agent or vehicle, for delivering the compound or compounds in question to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier.
  • carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • an effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay development.
  • an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence.
  • An effective amount can be administered in one or more doses.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • treatment refers to obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms (such as tumor growth or metastasis), diminishment of extent of cancer, stabilized (i.e., not worsening) state of cancer, preventing or delaying spread (e.g., metastasis) of the cancer, preventing or delaying occurrence or recurrence of cancer, delay or slowing of cancer progression, amelioration of the cancer state, and remission (whether partial or total).
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • An "animal” includes any animal, such as, but not limited to; mammals including humans, gorillas and monkeys, mice rats, pigs horses, cats, dogs, rabbits, sheep deer, cows, and goats.
  • alkyl means a hydrocarbon radical having from one to ten carbon atoms, which can be a straight or branched chain, and including from zero to four carbon- carbon double or triple bonds.
  • Representative of such radicals are methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethyl- hexyl and the like.
  • dialkylammo refers to -NR 3 R b , wherein R a and R b are independently selected alkyl groups, defined above.
  • alkoxy as used herein means an alkyl, as defined above, having an oxygen atom, attached thereto.
  • Representative alkoxy groups include — methoxy, ethoxy, propoxy, tert- butoxy and the like.
  • alkoxycarbonyl as used herein means an alkoxy radical, as defined above, including a carbonyl wherein Y and Z are each independently alkyl, as de- group, as defined below, fined above.
  • amino as used herein means a -NH2 substituent.
  • NSC-87877 4 was identified as a hit from the NCI Diversity set, is a potent Shp2 and Shp1 inhibitor (Chen, L. et al., MoI. Pharmacol. 2006, 70, 562-570).
  • NSC-87877 potently inhibited Shp2 with an IC 50 of 0.318 + 0.049 ( ⁇ M), but lacks selectivity between human Shp2 and Shp1 in vitro.
  • NSC-87877 showed approximately 5-, 24-, 206-, 266-, and 475-fold selectivity for Shp2 over PTP1 B, HePTP, DEP1 , CD45, and LAR.
  • the oxindole 5 (NSC-1 17199) (obtained from the Developmental Therapeutics Program of the NCI/NIH; Milne, G., et al., J. Chem. Inf. Comput. Sci. 1986, 26, 159-68) was found to be a hit with only moderate potency (IC 50 47 ⁇ M).
  • Compounds with an oxindole core have been studied by other groups as potential therapeutic agents. (Fong, T. et al., Cancer Res. 1999, 59, 99-106; Sun, L, et al., J. Med. Chem. 1999, 42, 5120-5130).
  • Serum-starved HEK293 cells were pre-incubated with or without NSC-87877 and stimulated with EGF or mock-treated to determine its ability to inhibit Shp2 in the cells.
  • DiFMUP substrate assay of cell lysate Shp2 immunoprecipitates indicated Shp2 PTP activity increased 2.6-fold in response to EGF stimulation in the absence of NSC-87877 pretreatment whereas NSC-87877 incubation reduced basal Shp2 PTP activity by 45%.
  • the EGF-stimulated Shp2 activation was inhibited by 97% when cells were pretreated with 50 ⁇ M NSC-87877, seen in Figure 2.
  • NSC-87877 treatment did not inhibit EGF-stimulated Gab1 tyrosine phosphorylation or subsequent Shp2-Gab1 binding in HEK293 cells, indicating NSC-87877 does not affect EGF- activated signaling steps prior to Shp2 activation.
  • NSC-1 17199 also forms hydrogen bond with the B-ring sulfonic acid group at the backbone NH group of Arg-465, seen in Figure 3.
  • Arg-465 is a conserved residue in the PTP signature motif (motif 9) VHCSXGXG R[T/S]G located at the base of the PTP catalytic cleft (Andersen et al., 2001 ).
  • the A-ring sulfonic acid forms hydrogen bonds with the side-chain NH 3 group of Lys-280 and the side-chain NH 2 group of Asn-281.
  • Lys-280/Asn-281 are non-conserved PTP residues located adjacent to the phosphotyrosine recognition loop (motif 1 ) (Andersen et al., 2001 ).
  • the interaction between aromatic rings of the compound and the protein contributes to the binding through hydrophobic stabilization. This formed the basis of the design of the library of NSC-1 17199 analogs (with the isatin core).
  • the anionic groups on the isatin bind to the phosphate binding site of the PTP loop, shown as the grey tube in Figure 3, and to Arg262, Lys364 and Lys 366.
  • PTP inhibitors were developed that display selectivity for Shp2 over Shp1 inhibition.
  • the oxindole 5 appeared to fit well in the catalytic site suggesting the hydrazone unit should not be replaced by longer spacer groups, seen in Figures 1 and 3.
  • the model also suggested the sulfonic acid could be replaced with small polar groups e.g. sulfonamide and carboxylamide.
  • the library was biased to include small polar replacements of the nitro and sulfonic acid groups to interact with the two polar binding sites. These were mostly at the 2 and 3 positions of the A-ring and the C5 of the indole ring, respectively.
  • the hydrogen bonding interactions of the oxindole N-H group with Asp425 was thought to be optimal, and variation of N-H was limited to N-Me, as seen in Figure 4.
  • hydrazones (10, 14 and 16) were prepared by combining a 5-substituted isatin with commercially available hydrazines; the sulfonyl and carboxyl groups were elaborated with a further set of amines to provide sulfonamides and amides.
  • the novel oxindole hydrazone sulfonamide library 10 was developed using commercially available building blocks as shown in Figure 5.
  • the oxindolesulfonyl chloride 8 was obtained from commercially available isatin-5-sulfonic acid according to a literature reported procedure. (Lee, D., et al., J. Med. Chem. 2001, 44, 2015-2026).
  • lsatin-5-sulfonyl chloride was coupled to a series of requisite amines to obtain the sulfonamide library 9.
  • Some members of the isatin library 9 were isolated and analyzed by NMR and mass spectrometry. Attempts to purify and isolate other members of the library 9 were not successful, however crude isatinsulfonamides 9 were successfully used.
  • the hydrazone library 10 was obtained by microwave assisted coupling of the crude library 9 with an appropriate set of hydrazines in moderate yields.
  • the carboxylic acid library 14 was prepared from methyl indole-5-carboxylate 11a, seen in Figure 6.
  • Treatment of 11a with NBS produced a dibromooxindole intermediate (Parrick, J., et al., J. Chem. Soc, Perkin Trans. 1 1989, 2009-2015) 12 in moderate yield, which was then converted into the desired library 14 in good yields by microwave assisted coupling with the requisite hydrazines.
  • Hydrolysis of 12 is used to generate intermediate isatin 13.
  • a series of carboxylamides 15 were prepared from the pentafluorophenyl ester of indole-5-carboxylic acid 11 b, seen in Figure 6.
  • the libraries 10, 14, and 16 were analyzed by NMR ( 1 H and 13 C), low and high resolution mass spectroscopy.
  • the 1 H NMR spectra of these compounds indicated formation a single stereoisomer with > 95% purity. Isatin hydrazones have been reported to exist in the Z configuration in solution, presumably due to the intramolecular hydrogen bonding between NH of the hydrazone linkage and the carbonyl group of the indolinone.
  • the analysis of the 13 C NMR spectra of the final compounds of the library 10 (10a-e, 10h, 10i, 10m, 10o, 10q) revealed oxindole carbonyl chemical shifts around 163 ppm, indicative of the Z-hydrazone stereochemical configuration.
  • Shp2 are shown in Figure 7. These compounds were further screened against Shp1 and PTP1 B to determine their selectivity. It was found that the carboxylic acid, sulfonamides, and carboxylamides at the 5-position of the oxindole moiety and nitro or carboxylic acid functional groups at the ortho-, meta- or para-positions of the phenylhydrazone moiety gave rise to the best Shp2 PTP inhibitory activity.
  • the b/s-carboxylic acid derivatives 14a and 14b displayed IC 50 0.8 and 15 DM inhibitory activity, respectively, with 20 and 5 fold Shp2 selectivity.
  • the compounds that lack the 5- position carboxylic acid, carboxyamides or sulfonamide groups (18a-e, Figure 6) showed poor activity (IC 50 > 60 ⁇ M, data not shown) indicating that the 5-substitution with polar groups (carboxylic acid, sulfonamide or carboxyamide) is important for activity and suggesting that the interactions in this region with Lys366 and Arg362, seen in Figure 8, are pivotal.
  • the orientation of the hydrazine-aromatic ring positions the carboxylic acid moiety of 14a, seen in Figures 8(a) and (b), so that it is capable of undergoing additional hydrogen bond interactions with Cys459, Gly464 and Ilu463 in the catalytic site.
  • This site binds substrate phosphotyrosine residues, therefore it is not surprising that the carboxylate ion binds better than the nitro group.
  • the indole nitrogen atoms do not overlay well, but both show a hydrogen bonding interaction with Shp2 amino acid residues (Asp425 in the case of NSC-1 17199 and Glu361 with 14a). These observations are in agreement with the design strategy to include both a polar group and phosphate mimic as a model for Shp2 inhibition.
  • the lead compound 14a was docked into the Shp1 PTP-catalytic site (using the X-ray crystal structure from pdb 1 FPR 34 ), as shown in Figure 8(b). In its lowest energy docking pose 14a displayed a weaker binding affinity (by 1.9 kcal), which may explain its selectivity towards Shp2.
  • High resolution mass spectroscopy was carried out on an Agilent 6210 LC/MS (ESI-TOF). Microwave reactions were performed in CEM 908005 model and Biotage initiator 8 machines. HPLC analysis was performed using a JASCO HPLC system equipped with a PU-2089 Plus quaternary gradient pump and a UV-2075 Plus UV-VIS detector, using an Alltech Kromasil C- 18 column (150 x 4.6 mm, 5 ⁇ m).
  • Thin layer chromatography was performed using silica gel 60 F254 plates (Fisher), with observation under UV when necessary.
  • Anhydrous solvents acetonitrile, dimethyl formamide, ethanol, isopropanol, methanol and tetrahydrofuran
  • HPLC grade solvents methanol, acetontrile and water
  • PTP phosphatase activity was measured using the fluorogenic 6, 8-difluoro-4- methylumbelliferyl phosphate (DiFMUP, from Molecular Probes) as the substrate.
  • DIFMUP fluorogenic 6, 8-difluoro-4- methylumbelliferyl phosphate
  • Each reaction contained 25 mM MOPS (pH 7.0), 50 mM NaCI, 0.05% Tween-20, 1 mM DTT, 20 ⁇ M DiFMUP, 10 nM Microcystin LR, 20 nM PTP (Shp2, Shp1 or PTP1 B), (See, Chen, L et al. MoI. Pharmacol. 2006, 70, 562-570) and 5 ⁇ l test compound or dimethyl sulfoxide (DMSO, solvent) in a total reaction volume of 100 ⁇ l in black 96-well plate.
  • DMSO dimethyl sulfoxide
  • IC 50 was defined as the concentration of an inhibitor that caused a 50% decrease in the PTP activity.
  • IC 50 determination 8 concentrations of compounds at 1/3 dilution ( ⁇ 0.5 log) were tested. Each experiment was performed in triplicate and IC 50 data were derived from at least three independent experiments.
  • the curve- fitting program Prism 4 (GraphPad Software) was used to calculate the IC 50 value.
  • a yellow solid product was obtained from 2,3-dioxo-2,3-dihydro-1 H-indole-5-sulfonyl chloride and 4-chlorobenzylamine in a similar manner as described for preparation of 2,3-dioxo-2,3- dihydro-1 H-indole-5-sulfonic acid dimethylamide.
  • the pure compound 2,3-dioxo-2,3-dihydro- 1 H-indole-5-sulfonic acid 4-chlorobenzylamide was obtained after trituration with ethyl acetate as a yellow solid; 57%.
  • Example 6 The general procedure for synthesis of isatin library 10.
  • Method A A mixture of the crude intermediate from library 9 (100 mg) and hydrazinobenzoic acid (1 eq.) in ethanol (1 ml) with hydrochloric acid (2 drops 1 M aq.) was heated in the Biotage microwave reactor at 120 0 C for 15 min. A yellow solid precipitated on cooling the reaction vial in an ice bath. The solid obtained was filtered and washed with methanol to give the pure product 10. The yields for these 2 steps were in the range of 15-80%.
  • Method B A mixture of the pure isatin 9a-c (0.419 mmol) and the appropriate hydrazine (0.461 mmol) in ethanol (3 ml) with hydrochloric acid (2 drops 1 M aq.) was heated in the Biotage microwave reactor at 120 0 C for 15 min. A yellow solid was precipitated on cooling in an ice bath. The solid obtained was filtered and washed with methanol to provide the pure final product.
  • Yellow solid product was obtained(43%) from 2,3-Dioxo-2,3-dihydro-1 H-indole-5-sulfonic acid 4-chlorobenzylamide and 2-nitrophenylhydrazine in a similar manner as described for preparation of 3-[(2-Nitrophenyl)hydrazono]-2-oxo-2,3-dihydro-1 H-indole-5-sulfonic acid dimethylamide. 43%.
  • Methyl dibromo-oxindole carboxylate 9 (40 mg, 0.1 14 mmol) was suspended in HCI (aq. 4 M, 2.00 ml) in a microwave vial and heated at 150 8 C for 5 min.
  • the intermediate 13 was not isolated, as seen in Figure 6.
  • 2-Hydrazinylbenzoic acid (23 mg, 0.126 mmol) was added to the reaction mixture and heated using the Biotage microwave reactor at 150 8 C for 15 min.
  • Pentafluorophenyl 1 H-indole-5-carboxylate intermediate for 15.
  • pentafluorophenyl trifluoroacetate 1.068 ml, 6.20 mmol
  • pyridine 0.281 ml
  • the reaction mixture (a suspension was obtained at this stage) was stirred at room temperature under inert atmosphere for approximately 30 minutes.
  • the reaction mixture was poured into ether (40 ml) and diluted with ethyl acetate (2 x 50 ml).
  • NCI Diversity Set chemical library of 1981 compounds was provided by the NCI Developmental Therapeutics Program. After the initial identification of NSC-87877 from the NCI Diversity Set, the authentic, 98% pure NSC-87877 [8-hydroxy-7-(6- sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid] was obtained from Acros for subsequent experiments.
  • Recombinant PTP Proteins Plasmids for expression of glutathione S-transferase (GST)-PTP fusion proteins of human Shp2 (residues 205-593), Shp1 (residues 205-597), and PTP1 B (residues 1 -435) were constructed in pGEX-2T by PCR subcloning techniques. A plasmid for GST fusion protein of human HePTP (residues 1 -399) was constructed in pGEX-2T-KG.
  • GST glutathione S-transferase
  • GST-PTP fusion proteins were expressed in E. coli DH5 ⁇ and affinity purified with glutathione Sepharose. After elution from glutathione affinity column, GST-fusion proteins were dialyzed with dialysis buffer (12.5 mM Tris-CI, pH 7.5, 25 mM NaCI, 1 mM dithiothreitol (DTT), and
  • PTP Activity Assay PTP activity was measured using the fluorogenic 6,8-difluoro-4- methylumbelliferyl phosphate (DiFMUP, from Invitrogen) as the substrate. Unless otherwise specified, each reaction contained 25 mM MOPS (pH 7.0), 50 mM NaCI, 0.05% Tween-20, 1 mM DTT, 20 ⁇ M DiFMUP, 10 nM Microcystin LR, 20 nM GST-PTP, and 5 Dl test compound or dimethyl sulfoxide (DMSO, solvent) in a total reaction volume of 100 Dl in black 96-well plates. Reaction was initiated by addition of DiFMUP and the incubation time was 30 min at room temperature.
  • DiFMUP fluorogenic 6,8-difluoro-4- methylumbelliferyl phosphate
  • DiFMU fluorescence signal was measured at an excitation of 355 nm and an emission of 460 nm with a Wallac Victor 2 1420 plate reader.
  • IC 50 was defined as the concentration of an inhibitor that caused a 50% decrease in the PTP activity.
  • 8 concentrations of NSC-87877 at 1/3 dilution ( ⁇ 0.5 log) were tested.
  • the ranges of NSC-87877 concentrations used in each PTP assay were determined from preliminary trials. Each experiment was performed in triplicate and IC 50 data were derived from at least three independent experiments.
  • the curve-fitting program Prism 4 (GraphPad Software) was used to calculate the IC 50 value.
  • Computer docking was performed using the X-ray crystal structure of human Shp2 (PDB identification code: 2SHP) (Hof P, et al. Ce// 1998, 92(4) :441 -450) using the GLIDE (Grid-Based Ligand Docking from Energetics, as part of the FirstDiscovery Suite from Schr ⁇ dinger, L.L.C.) program (Friesner RA, et al. J Med Chem 2004, 47(7):1739-1749; Halgren TA, et al. J Med Chem 2004, 47(7):1750-1759).
  • the N-SH2 domain of Shp2, which blocks the catalytic site was removed from the 3D structure prior to the computer docking analysis.
  • pcDNA5/FRT/TO-Gab1 PH-Shp2 ⁇ N and pOG44 was then co-transfected into the Flp-ln-T-Rex-293 cells (Invitrogen). Transfected cells were selected in Dulbecco's modified Eagle medium (DMEM)/10% tetracycline-free fetal bovine serum (FBS) medium containing 100 ⁇ g/ml hygromycin.
  • DMEM Dulbecco's modified Eagle medium
  • FBS tetracycline-free fetal bovine serum
  • Cells were cultured in DMEM/10% FBS. Sub-confluent cells were serum-starved in DMEM/0.1 % BSA for 18 h prior to treatment with NSC-87877 and stimulation with EGF or PMA. Cells were lysed on ice with Lysis Buffer A (50 mM Tris-HCI, pH 7.5, 150 mM NaCI, 1 mM EDTA, 1 mM EGTA, 25 mM NaF, 5 mM sodium pyrophosphate, 1 mM DTT, 20 mM p-nitrophenyl phosphate, 1 % Triton X-100).
  • Lysis Buffer A 50 mM Tris-HCI, pH 7.5, 150 mM NaCI, 1 mM EDTA, 1 mM EGTA, 25 mM NaF, 5 mM sodium pyrophosphate, 1 mM DTT, 20 mM p-nitrophenyl phosphate, 1 % Triton
  • Shp2 or Shp1 in cell lysate supernatants were immunoprecipitated with an antibody to Shp2 or an antibody to Shp1 (Santa Cruz) plus Protein A-Sepharose for 2 h at 4 C. lmmunoprecipitates were washed twice with the PTP lysis buffer and twice with Reaction Buffer (20 mM Hepes pH 7.4, 1 mM EDTA, 5% Glycerol, 1 mM DTT) (Tartaglia M, et al. Nat. Genet. 2003, 34(2):148-150).
  • Shp2 or Shp1 immune complex was resuspended in 100 Dl Reaction Buffer containing 50 DM DiFMUP and then incubated at room temperature for 20 min. After a brief centrifugation, supernatants were transferred into 96-well plates and the DiFMU fluorescence signal was measured. The remaining immune complexes were used for immunoblotting analysis of Shp2 or Shp1.
  • Ras Activation Assay Active Ras in MDA-MB-468 cells was detected by means of Ras-GTP bound to a GST fusion protein of the Ras-GTP binding domain of Raf fragment (GST-RBD) (Cunnick JM, et al. J Biol. Chem. 2002, 277(1 1 ):9498-9504) followed by immunoblotting with an anti-Ras antibody (Santa Cruz).

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Abstract

L'invention concerne la protéine tyrosine phosphatase (PTP) Shp2 qui est une PTP non réceptrice qui est impliquée dans une signalisation de cellule et une régulation de prolifération cellulaire, une différenciation, et une migration. Shp2 régule l'activation des kinases qui sont impliquées dans la pathogenèse d'un carcinome humain. NSC-117199 a été identifié comme un inhibiteur potentiel de la protéine tyrosine phosphatase (PTPa) Shp2. Une librairie d'analogues focalisée comportant une structure d'isatine a été conçue et évaluée en ce qui concerne l'inhibition des activités de PTP Shp2 et Shp1. Plusieurs composés ont été identifiés qui inhibent de manière sélective Shp2 sur Shp1 et PTP1B avec une activité faible à sous-micromolaire. Des procédés sont également décrits pour l’inhibition d'une protéine tyrosine phosphatase dans une cellule et de traitement du cancer à travers une inhibition sélective de Shp2.
PCT/US2009/042305 2008-04-30 2009-04-30 Inhibition de la protéine tyrosine phosphatase shp2/ptpn11 par nsc-117199 et analogues Ceased WO2009135000A2 (fr)

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WO2011110546A3 (fr) * 2010-03-08 2012-01-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Composition pharmaceutique comprenant un inhibiteur de shp-2
WO2012041524A1 (fr) 2010-10-01 2012-04-05 Max-Delbrück-Centrum Für Molekulare Medizin (Mdc) Hydrazonopyrazolones comme inhibiteurs de la protéine tyrosine phosphatase
WO2013033133A1 (fr) * 2011-09-01 2013-03-07 Novartis Ag Utilisation d'un composé organique dans le traitement du syndrome de noonan
US8623906B2 (en) 2009-04-17 2014-01-07 H. Lee Moffitt Cancer Center And Research Institute, Inc. Carboxy isatin hydrazones and their esters as Shp2 inhibitors
CN105362270A (zh) * 2014-08-18 2016-03-02 天津药物研究院 2，4-二羟基查尔酮类衍生物抗Noonan综合征的用途
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
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WO2021091956A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
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US6964977B2 (en) * 2000-09-01 2005-11-15 Smithkline Beecham Corporation Oxindole derivatives
WO2007117699A2 (fr) * 2006-04-07 2007-10-18 University Of South Florida Inhibition de la proteine tyrosine phosphatase shp2/ptpn11 par nsc-87877, nsc-117199 et leurs analogues

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US8623906B2 (en) 2009-04-17 2014-01-07 H. Lee Moffitt Cancer Center And Research Institute, Inc. Carboxy isatin hydrazones and their esters as Shp2 inhibitors
WO2011110546A3 (fr) * 2010-03-08 2012-01-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Composition pharmaceutique comprenant un inhibiteur de shp-2
WO2012041524A1 (fr) 2010-10-01 2012-04-05 Max-Delbrück-Centrum Für Molekulare Medizin (Mdc) Hydrazonopyrazolones comme inhibiteurs de la protéine tyrosine phosphatase
WO2013033133A1 (fr) * 2011-09-01 2013-03-07 Novartis Ag Utilisation d'un composé organique dans le traitement du syndrome de noonan
US9034909B2 (en) 2011-09-01 2015-05-19 Novartis Ag Use of organic compound for the treatment of Noonan Syndrome
CN105362270A (zh) * 2014-08-18 2016-03-02 天津药物研究院 2，4-二羟基查尔酮类衍生物抗Noonan综合征的用途
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
WO2020180770A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2021091967A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
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WO2021108683A1 (fr) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2022140427A1 (fr) 2020-12-22 2022-06-30 Qilu Regor Therapeutics Inc. Inhibiteurs de sos1 et utilisations associées
WO2025137507A1 (fr) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Inhibiteurs de sos1 et leurs utilisations

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