A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers
文献类型：期刊论文
| 作者 | Feng, Juanjuan2; Xiao, Xuanzheng3; Xia, Xinting2; Min, Jian1; Tang, Weiying2; Shi, Xinyi3; Xu, Ke4; Zhou, Guizhen4; Li, Kangkang1; Shen, Panpan1 |
| 刊名 | CANCER CELL
 |
| 出版日期 | 2025-10-13 |
| 卷号 | 43期号:10页码:32 |
| ISSN号 | 1535-6108 |
| DOI | 10.1016/j.ccell.2025.07.006 |
| 英文摘要 | 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. |
| WOS关键词 | KRAS(G12C) ; POTENT |
| 资助项目 | National Natural Science Foundation of China[82472677] ; National Natural Science Foundation of China[82122045] ; National Natural Science Foundation of China[22494694] ; National Natural Science Foundation of China[82273767] ; National Natural Science Foundation of China[82341210] ; National Natural Science Foundation of China[82404653] ; National Natural Science Foundation of China[223B2704] ; Natural Science Foundation of Shanghai[23ZR1418900] ; Innovative Research Team of High-Level Local Universities in Shanghai[SHSMU-ZDCX2021080 2] ; Science and Technology Commission of Shanghai Municipality[23YF1435700] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001599003400010 |
| 出版者 | CELL PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/320463]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Guo, Rey-Ting; Zhang, Ao; Pang, Xiufeng |
| 作者单位 | 1.Hubei Univ, Sch Life Sci, State Key Lab Biocatalysis & Enzyme Engn, Hubei Hongshan Lab, Wuhan 430062, Peoples R China 2.East China Normal Univ, Changning Matern & Infant Hlth Hosp, Shanghai Frontiers Sci Ctr Genome Editing & Cell, Inst Biomed Sci,Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China 3.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, State Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Shanghai Jiao Tong Univ, Shanghai Inst Immunol, State Key Lab Syst Med Canc, Sch Med, Shanghai 200030, Peoples R China 6.Zhejiang Univ, Life Sci Inst, Hangzhou 310058, Zhejiang, Peoples R China 7.Southern Med Univ, Affiliated Fengxian Hosp, Guangzhou 510515, Guangdong, Peoples R China 8.Fudan Univ, Shanghai Canc Ctr, Canc Inst, Shanghai Med Coll, Shanghai 200032, Peoples R China 9.Xinjiang Normal Univ, Coll Life Sci, Urumqi 830054, Peoples R China 10.Renmin Univ China, Inst Math Sci, Beijing 100872, Peoples R China |
| 推荐引用方式 GB/T 7714 | Feng, Juanjuan,Xiao, Xuanzheng,Xia, Xinting,et al. A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers[J]. CANCER CELL,2025,43(10):32. |
| APA | Feng, Juanjuan.,Xiao, Xuanzheng.,Xia, Xinting.,Min, Jian.,Tang, Weiying.,...&Pang, Xiufeng.(2025).A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers.CANCER CELL,43(10),32. |
| MLA | Feng, Juanjuan,et al."A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers".CANCER CELL 43.10(2025):32. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。