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

The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based on the structural analysis of MRTX1133 in complex with KRAS, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (, , and ) that showed higher potency in suppressing the clonogenic growth of KRAS-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS with IC 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 and potency of these new inhibitors call for further profiling.