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.

Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance.

Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1-1,2,3-triazole derivative as a highly potent and orally available OXPHOS inhibitor that effectively blocked the activity of mitochondrial complex I. specifically compromised the mitochondrial oxygen consumption of high-OXPHOS lung cancer cells but not that of low-OXPHOS lung cancer cells or normal cells in the low nanomolar range.

Feedback activation of EGFR/wild-type RAS signaling axis limits KRAS inhibitor efficacy in KRAS-mutated colorectal cancer.

Colorectal cancer (CRC), which shows a high degree of heterogeneity, is the third most deadly cancer worldwide. Mutational activation of KRAS occurs in approximately 10-12% of CRC cases, but the susceptibility of KRAS-mutated CRC to the recently discovered KRAS inhibitor MRTX1133 has not been fully defined. Here, we report that MRTX1133 treatment caused reversible growth arrest in KRAS-mutated CRC cells, accompanied by partial reactivation of RAS effector signaling.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in -mutant lung cancer.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in -mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer -mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis.