2. Academic Validation
  3. A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers

  • Cancer Cell. 2025 Jul 25:S1535-6108(25)00310-1. doi: 10.1016/j.ccell.2025.07.006.
Juanjuan Feng 1,  Xuanzheng Xiao 2,  Xinting Xia 1,  Jian Min 3,  Weiying Tang 1,  Xinyi Shi 2,  Ke Xu 4,  Guizhen Zhou 4,  Kangkang Li 3,  Panpan Shen 3,  Rujuan Bao 5,  Shuyao Wu 5,  Mengjia Lin 6,  Kun Yuan 1,  Zhengke Lian 1,  Longmiao Hu 1,  Na Li 1,  Zhengzhen Wu 1,  Xiaotong Zhai 1,  Xiaogu Liu 7,  Kewen Hu 8,  Jun Wu 1,  Chunyong Ding 2,  Huixin Zhao 9,  Xinqi Gong 10,  Sulin Zhang 4,  Jianping Jin 6,  Dali Li 1,  Mingyao Liu 1,  Youqiong Ye 5,  Buyong Ma 2,  Rey-Ting Guo 11,  Ao Zhang 12,  Xiufeng Pang 13
Affiliations

Affiliations

  • 1 Changning Maternity and Infant Health Hospital, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Hongshan Laboratory, School of Life Sciences, Hubei University, Wuhan 430062, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 7 Southern Medical University Affiliated Fengxian Hospital, Southern Medical University, Guangdong, Guangzhou 510515, China.
  • 8 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 9 College of Life Science, Xinjiang Normal University, Urumqi 830054, China.
  • 10 Institute for Mathematical Sciences, Renmin University of China, Beijing 100872, China.
  • 11 Zhejiang Key Laboratory of Medical Epigenetics, Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China. Electronic address: guoreyting@hznu.edu.cn.
  • 12 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: ao6919zhang@sjtu.edu.cn.
  • 13 Changning Maternity and Infant Health Hospital, Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China; College of Life Science, Xinjiang Normal University, Urumqi 830054, China. Electronic address: xfpang@bio.ecnu.edu.cn.
PMID: 40780213 DOI: 10.1016/j.ccell.2025.07.006
Abstract

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 KRASG12D 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 KRASG12C 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.

Keywords

KRAS; KRAS signaling; cancer therapeutics; degrader; immune evasion; oncogenic KRAS; pan-KRAS inhibitor; targeted protein degradation; therapy resistance; tumor immune microenvironment.

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