克拉斯
化学
Atom(片上系统)
脚(韵律)
立体化学
组合化学
突变
药物化学
生物化学
并行计算
基因
文学类
艺术
计算机科学
作者
Jürgen Ramharter,Dirk Kessler,Peter Ettmayer,Marco H. Hofmann,Thomas Gerstberger,Michael Gmachl,Tobias Wunberg,Christiane Kofink,Michael P. Sanderson,Heribert Arnhof,Gerd Bader,Klaus Rumpel,Andreas Zöphel,Renate Schnitzer,Jark Böttcher,Jonathan C. O’Connell,Rachel L. Mendes,David C. S. Richard,Nikolai Pototschnig,Irene Weiner
标识
DOI:10.1021/acs.jmedchem.0c01949
摘要
KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884SOS1 and A73KRAS is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of BI-3406. Combination with the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRASG13D mutant colorectal tumor cells, demonstrating the utility of BI-3406 to probe SOS1 biology. These findings challenge the dogma that large molecules are required to disrupt challenging PPIs. Instead, a "foot in the door" approach, whereby single atoms or small functional groups placed between key PPI interactions, can lead to potent inhibitors even for challenging PPIs such as SOS1-KRAS.
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