Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction
Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction
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DOI：
10.1073/pnas.1812963116
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发表时间：
2019-02-12
影响因子：
11.1
通讯作者：
Bader, Benjamin
中科院分区：
文献类型：
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作者：
Hillig, Roman C.;Sautier, Brice;Bader, Benjamin
自20世纪80年代后期以来，RAS基因突变已被认为是人类癌症中发生率高的主要癌基因。这种突变降低了小GTP酶RAS水解GTP的能力，使这种分子开关保持在组成型活性GTP结合形式，驱动未经检查的致癌下游信号传导。降低活性RAS水平的一种策略是靶向鸟嘌呤核苷酸交换因子，其允许RAS从非活性GDP结合状态循环到活性GTP结合形式。在这里，我们描述了有效的和细胞活性的小分子抑制剂，有效地破坏KRAS和其交换因子SOS 1之间的相互作用，一系列生物物理技术证实的作用模式的识别。使用KRAS（G12 C）-SOS 1、SOS 1和SOS 2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-SOS 1复合物的形成，这些抑制剂阻断KRAS与GTP的重新加载，从而产生抗增殖活性。最终化合物23（BAY-293）选择性抑制KRAS-SOS 1相互作用，IC 50 1980为21 nM，是未来研究的有价值的化学探针。
Since the late 1980s, mutations in the RAS 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(G12C)-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 IC50 1980s of 21 nM and is a valuable chemical probe for future investigations.