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Ref Type Journal Article
PMID (27362227)
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.
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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SHP099 SHP099 11 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SHP099 SHP-099|SHP 099 SHP2 Inhibitor 20 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
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
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