Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment.

As an oncogenic phosphatase, SHP2 acts as a converging node in the RTK-RAS-MAPK signaling pathway in cancer cells and suppresses antitumor immunity by passing signals downstream of PD-1. Here, we utilized the extra druggable pocket outside the previously identified SHP2 allosteric tunnel site by the (6,5 fused), 6 spirocyclic system. The optimized compound, , exhibited a SHP2 binding of 0.37 nM, SHP2 enzymatic IC of 1.9 nM, KYSE-520 antiproliferative IC of 7.4 nM and p-ERK inhibitory IC of 0.23 nM. For , an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of and the p-ERK inhibition in tumors. Currently, is undergoing clinical trials as a potential anticancer agent.