22:T497,Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1H-1,2,3-triazole derivative HP661 as a highly potent and orally available OXPHOS inhibitor that effectively blocked the activity of mitochondrial complex I. HP661 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. Notably, mitogen-activated protein kinase kinase (MEK) inhibitor (trametinib)-resistant lung cancer cells with high levels of OXPHOS also showed marked sensitivity to HP661, as indicated by decreased clonogenic growth and increased cell apoptosis upon treatment. In a mouse model of high-OXPHOS lung cancer, HP661 treatment not only significantly suppressed tumor growth but also augmented the therapeutic efficacy of trametinib by impairing tumor mitochondrial respiration. In summary, we identified HP661 as a highly effective OXPHOS inhibitor to abrogate the growth of high OXPHOS-dependent tumors and conquer high OXPHOS-mediated drug resistance.23:T43f,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 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.24:T4c5,KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. MCB-294 engages the switch-II pocket through a water-mediated hydrogen-bond network and selectively inhibits KRAS over NRAS and HRAS. It effectively suppresses oncogenic KRAS signaling, inhibits the growth of KRAS-dependent cancer cells and patient-derived organoids, and reduces tumor progression in multiple preclinical models. MCB-294 also demonstrates superior activity compared to the inactive-state selective pan-KRAS inhibitor Bl-2865 and the KRAS^G12D inhibitor MRTX1133. Building upon MCB-294 as a pan-KRAS-targeting warhead, we further develop MCB-36, a von Hippel-Lindau (VHL)-recruiting pan-KRAS degrader that induces sustained KRAS degradation. Notably, both MCB-294 and MCB-36 effectively suppress KRAS^G12C inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. These findings highlight a promising therapeutic strategy for broadly targeting KRAS-driven tumors and overcoming drug resistance.

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