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
{"title":"Targeting cancer with small-molecule pan-KRAS degraders","authors":"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","doi":"10.1126/science.adm8684","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"385 6715","pages":""},"PeriodicalIF":45.8000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.adm8684","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Science is a leading outlet for scientific news, commentary, and cutting-edge research. Through its print and online incarnations, Science reaches an estimated worldwide readership of more than one million. Science’s authorship is global too, and its articles consistently rank among the world's most cited research.
Science serves as a forum for discussion of important issues related to the advancement of science by publishing material on which a consensus has been reached as well as including the presentation of minority or conflicting points of view. Accordingly, all articles published in Science—including editorials, news and comment, and book reviews—are signed and reflect the individual views of the authors and not official points of view adopted by AAAS or the institutions with which the authors are affiliated.
Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit recognition by the wider scientific community and general public provided by publication in Science, beyond that provided by specialty journals. Science welcomes submissions from all fields of science and from any source. The editors are committed to the prompt evaluation and publication of submitted papers while upholding high standards that support reproducibility of published research. Science is published weekly; selected papers are published online ahead of print.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
