SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) involved in cell growth and differentiation via the MAPK signaling pathway and also function in the programed cell death pathway (PD-1/PD-L1), which significant therapeutic interest in multiple cancer-related diseases and potential immunomodulator. SHP099 Hydrochloride is a hydrochloride form of SHP099. SHP099 is a highly potent, selective and orally bioavailable small-molecule SHP2 inhibitor with an IC50 value of 0.071 μM[1]. SHP099 can inhibit cell proliferation (KYSE-520 model) with an IC50 value of 1.4 μM. Moreover, SHP099 stabilizes SHP2 in an auto-inhibited conformation. by suppressing RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro. SHP099 shows no activity against SHP1, the closest homologue of SHP2 sharing 61% amino acid sequence identity, supporting its high degree of target selectivity. It inhibits p-ERK with an IC50 of ~0.25 μM in SHP2-dependent MDA-MB-468 and KYSE520 cells, but not in A2058 cells. No effect is observed on p-AKT levels across the same cells. SHP099 inhibits MAPK signalling and proliferation in RTK-dependent cells through direct on-target inhibition of SHP2[2]. In addition, SHP099 can selective inhibit cell growth of leukemia-associated SHP2E69K mutant with the IC50 of 1.73±0.52μM and inhibit active ERK, induced PARP cleavage of the mutant[5]. For wild type SHP2 and its oncogenic mutation E76K, inhibition to E76K was much weaker while the structure was identical with the wild type, suggesting more chances for highly selective, novel therapy of different SHP- mutant[4].
作用机制
SHP099 will block active site of SHP2 by inhibiting phosphatase activity[4].
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