BGC1201: A potent allosteric SHP2 inhibitor with broad antitumor activity in lung, pancreatic, and esophageal cancer xenografts

BGC1201 is a novel allosteric SHP2 inhibitor developed via fragment-based drug design (FBDD). It potently inhibited SHP2-WT phosphatase with an IC 50 of 2.47 nM and suppressed p-ERK expression in NCI-H358 cells with an IC 50 of 17.3 nM. BGC1201 showed weak inhibition of the hERG potassium channel, with an IC 50 value > 40 μM, suggesting a low hERG-related liability in vitro. In a panel of 14 tumor cell lines, BGC1201 showed antiproliferative activity against 12 lines, with IC 50 values ranging from 0.0236 to 8.66 μM, while sparing normal HUVEC cells. In nude mouse xenograft models of human lung (NCI-H358), pancreatic (MIA PaCa-2), and esophageal (KYSE-520) cancers, oral administration of BGC1201 produced significant tumor growth inhibition with a dose-dependent trend. Western blot analysis further confirmed that BGC1201 reduced p-ERK levels in tumor tissues in a time-dependent manner. Pharmacokinetic evaluation in rats showed that BGC1201 achieved measurable oral exposure and was eliminated through multiple metabolic and excretory pathways. These findings support BGC1201 as a promising candidate for further anticancer drug development.