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

IF 44.5 1区 医学 Q1 CELL BIOLOGY
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, Xiufeng Pang
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引用次数: 0

摘要

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。在这里,我们报告了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,我们进一步开发了MCB-36,一种von Hippel-Lindau (VHL)招募的pan-KRAS降解剂,可诱导持续的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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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
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.
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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