近日，华东师范大学教授庞秀峰及其小组报道了一种泛KRAS抑制剂及其衍生的降解剂在KRAS驱动的癌症中具有多方面的抗肿瘤功效。相关论文于2025年8月7日发表在《癌细胞》杂志上。

课题组报道了MCB-294的发现，这是一种有效的双态泛KRAS抑制剂，能够结合活性（GTP结合）和非活性（GDP结合）形式的KRAS。MCB-294通过水介导的氢键网络与开关-II口袋接合，并选择性地抑制NRAS和HRAS之上的KRAS。在多种临床前模型中，它有效抑制致癌KRAS信号，抑制KRAS依赖性癌细胞和患者来源的类器官的生长，并减缓肿瘤进展。与非活性状态的选择性泛KRAS抑制剂Bl-2865和KRASG12D抑制剂MRTX1133相比，MCB-294也显示出更高的活性。在MCB-294作为pan-KRAS目标战斗部的基础上，课题组进一步开发了MCB-36，一种von Hippel-Lindau （VHL）招募的pan-KRAS降解剂，诱导持续的KRAS降解。值得注意的是，MCB-294和MCB-36都能有效抑制KRASG12C抑制剂耐药的癌细胞，重塑肿瘤免疫微环境。这些发现突出了广泛靶向KRAS驱动肿瘤和克服耐药性的有希望的治疗策略。

据悉，KRAS仍然是一个具有挑战性的治疗靶点，目前可用的有效抑制剂有限。

附：英文原文

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

Author: Juanjuan Feng, Xuanzheng Xiao, Xinting Xia, Jian Min, Weiying Tang, Xinyi Shi, Ke Xu, Guizhen Zhou, Kangkang Li, Panpan 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

Issue&Volume: 2025-08-07

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.

DOI: 10.1016/j.ccell.2025.07.006

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00310-1