The
breakthrough in drug development of KRASG12C inhibitors
provides inspiration for targeting alternative KRAS mutations, especially
the most prevalent KRASG12D variant. Based on the structural
analysis of MRTX1133 in complex with KRASG12D, a comprehensive
structure–activity study was conducted, which led to the discovery
of several compounds (22, 28, and 31) that showed higher potency in suppressing the clonogenic
growth of KRASG12D-dependent cancer cells. These new compounds
markedly and selectively inhibited the binding of RBD peptide to GTP-bound
KRASG12D with IC50 values between 0.48 and 1.21
nM. These new inhibitors were found to have dose-dependent anti-tumor
efficacy in the AsPC-1 xenograft mouse models with a tumor growth
inhibition of approximately 70% at a dose of 20 mg/kg twice daily
(i.p.). Despite the non-optimal pharmacokinetic properties similar
to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further
profiling.