Targeting cancer with small-molecule pan-KRAS degraders

IF 5.6 2区化学 Q1 CHEMISTRY, MEDICINAL

Journal of Chemical Information and Modeling Pub Date : 2024-09-19 DOI:10.1126/science.adm8684

Johannes Popow, William Farnaby, Andreas Gollner, Christiane Kofink, Gerhard Fischer, Melanie Wurm, David Zollman, Andre Wijaya, Nikolai Mischerikow, Carina Hasenoehrl, Polina Prokofeva, Heribert Arnhof, Silvia Arce-Solano, Sammy Bell, Georg Boeck, Emelyne Diers, Aileen B. Frost, Jake Goodwin-Tindall, Jale Karolyi-Oezguer, Shakil Khan, Theresa Klawatsch, Manfred Koegl, Roland Kousek, Barbara Kratochvil, Katrin Kropatsch, Arnel A. Lauber, Ross McLennan, Sabine Olt, Daniel Peter, Oliver Petermann, Vanessa Roessler, Peggy Stolt-Bergner, Patrick Strack, Eva Strauss, Nicole Trainor, Vesna Vetma, Claire Whitworth, Siying Zhong, Jens Quant, Harald Weinstabl, Bernhard Kuster, Peter Ettmayer, Alessio Ciulli

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Abstract

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

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用小分子泛 KRAS 降解剂靶向癌症

柯氏大鼠肉瘤病毒癌基因同源物（KRAS）蛋白的突变在癌症中非常普遍。然而，除了用半胱氨酸（G12C）取代第 12 位的甘氨酸（临床上可通过共价抑制剂对其进行药物治疗）外，解决致癌 KRAS 等位基因的小分子概念仍然难以捉摸。以三元复合物的生物物理和结构研究为指导，我们设计了一种杂多功能小分子，它能有效降解 17 种最常见致癌 KRAS 等位基因中的 13 种。与抑制作用相比，降解 KRAS 能在广泛的 KRAS 突变细胞系中产生更深远、更持久的通路调节作用，在杀死癌细胞的同时，还能挽救没有 KRAS 基因畸变的模型。致癌 KRAS 的药理降解具有耐受性，可导致体内肿瘤消退。这些发现共同揭示了用小分子降解剂解决 KRAS 驱动癌症的新途径。

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来源期刊

Journal of Chemical Information and Modeling 化学-化学综合

CiteScore

9.80

自引率

10.70%

发文量

529

审稿时长

1.4 months

期刊介绍： The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.