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|Ref Type||Journal Article|
|Authors||Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, Antonakos B, Chen CH, Chen Z, Cooke VG, Dobson JR, Deng Z, Fei F, Firestone B, Fodor M, Fridrich C, Gao H, Grunenfelder D, Hao HX, Jacob J, Ho S, Hsiao K, Kang ZB, Karki R, Kato M, Larrow J, La Bonte LR, Lenoir F, Liu G, Liu S, Majumdar D, Meyer MJ, Palermo M, Perez L, Pu M, Price E, Quinn C, Shakya S, Shultz MD, Slisz J, Venkatesan K, Wang P, Warmuth M, Williams S, Yang G, Yuan J, Zhang JH, Zhu P, Ramsey T, Keen NJ, Sellers WR, Stams T, Fortin PD|
|Title||Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.|
|Date||2016 07 07|
|Abstract Text||The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SHP099||SHP2 Inhibitor 9||SHP099 is an allosteric inhibitor of SHP2 that stabilizes SHP2 in its autoinhibited conformation, which reduces downstream signaling and potentially leads to decreased growth of receptor tyrosine kinase-driven tumors (PMID: 27362227, PMID: 31043123).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E||colorectal cancer||resistant||SHP099||Preclinical - Cell culture||Actionable||In a preclincial study, colorectal cancer cell lines harboring BRAF V600E demonstrated resistance to SHP099 in culture (PMID: 27362227).||27362227|
|NRAS mutant||hematologic cancer||predicted - resistant||SHP099||Preclinical||Actionable||In a preclinical study, hematopoietic cancer cell lines harboring NRAS mutations demonstrated resistance to SHP099 in cell culture (PMID: 27362227).||27362227|
|BRAF V600E||melanoma||no benefit||SHP099||Preclinical||Actionable||In a preclinical study, SHP099 did not inhibit proliferation or ERK activation in a melanoma cell line harboring BRAF V600E in culture (PMID: 27362227).||27362227|
|JAK2 V617F||hematologic cancer||sensitive||SHP099||Preclinical - Cell culture||Actionable||In a preclinical study, SHP099 inhibited proliferation of a hematopoietic cancer cell line harboring JAK2 V617F in culture (PMID: 27362227).||27362227|
|FLT3 exon 14 ins||acute myeloid leukemia||predicted - sensitive||SHP099||Preclinical - Pdx||Actionable||In a preclinical study, treatment with SHP099 resulted in reduction of CD45-positive leukemic cells and decreased splenomegaly in a human primary tumor-derived xenograft model of acute myeloid leukemia harboring a FLT3-ITD mutation (PMID: 27362227).||27362227|