Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3- d ]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRAS G12D Inhibitors.

The breakthrough in drug development of KRAS G12C inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS G12D variant. Based on the structural analysis of MRTX1133 in complex with KRAS G12D , 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 KRAS G12D -dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS G12D with IC 50 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.