A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers
Juanjuan Feng, Xuanzheng Xiao, Xinting Xia, Jian Min, Weiying Tang, Xinyi Shi, Ke Xu, Guizhen Zhou, Kangkang Li, Pan‐Pan Shen, Rujuan Bao, Shuyao Wu, Mengjia Lin, Kun Yuan, Zhengke Lian, Longmiao Hu, Na Li, Zhengzhen Wu, Xiaotong Zhai, Xiaogu Liu, Kewen Hu, Jun Wu, Chunyong Ding, Huixin Zhao, Xinqi Gong, Sulin Zhang, Jianping Jin, Dali Li, Mingyao Liu, Youqiong Ye, Buyong Ma, Rey-Ting Guo, Ao Zhang, Xiufeng Pang
Abstract
<h2>Summary</h2> 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 <i>KRAS</i>-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<sup>G12D</sup> 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<sup>G12C</sup> inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. These findings highlight a promising therapeutic strategy for broadly targeting <i>KRAS</i>-driven tumors and overcoming drug resistance.