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, JAB-3312, exhibited a SHP2 binding Kd of 0.37 nM, SHP2 enzymatic IC50 of 1.9 nM, KYSE-520 antiproliferative IC50 of 7.4 nM
and p-ERK inhibitory IC50 of 0.23 nM. For JAB-3312, an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI
in KYSE-520 xenograft model of mouse. JAB-3312 was well-tolerated
in animal models, and a close correlation was observed between the
plasma concentration of JAB-3312 and the p-ERK inhibition
in tumors. Currently, JAB-3312 is undergoing clinical
trials as a potential anticancer agent.