Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature	535	7610	2016 07 07	148-52	Nature

URL

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
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
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
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
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
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