Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany;
Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. doi: 10.1073/pnas.1812963116. Epub 2019 Jan 25.
Since the late 1980s, mutations in the genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC of 21 nM and is a valuable chemical probe for future investigations.
自 20 世纪 80 年代末以来，人们已经认识到基因中的突变是主要的致癌基因，在人类癌症中发生率很高。这种突变降低了小分子 GTP 酶 RAS 水解 GTP 的能力，使这种分子开关保持在持续激活的 GTP 结合形式，从而不受控制地驱动致癌的下游信号。减少活性 RAS 水平的一种策略是靶向鸟嘌呤核苷酸交换因子，它允许 RAS 从非活性 GDP 结合状态循环到活性 GTP 结合形式。在这里，我们描述了有效破坏 KRAS 和其交换因子 SOS1 之间相互作用的有效和细胞活性的小分子抑制剂的鉴定，通过一系列生物物理技术证实了这种作用模式。使用 KRAS-SOS1、SOS1 和 SOS2 的晶体结构阐明了结合位点、作用模式和选择性。通过阻止 KRAS-SOS1 复合物的形成，这些抑制剂阻止 KRAS 与 GTP 的重新加载，导致抗增殖活性。最终的化合物 23（BAY-293）以 21 nM 的 IC 选择性抑制 KRAS-SOS1 相互作用，是未来研究的有价值的化学探针。
