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Discovery of novel indazole derivatives as SOS1 agonists that activate KRAS signaling

[Display omitted] •Discovery of novel indazole-scaffold derivatives as SOS1 agonists.•Compound 11 displayed high activation potency on active RAS-GTP and ERK1/2 phosphorylation via a SOS1 dependent on-target mechanism.•These findings highlight an “activity cliff” example by a marginal structural mod...

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Published in:Bioorganic & medicinal chemistry 2023-10, Vol.93, p.117457, Article 117457
Main Authors: Liu, Lu, Song, Zhendong, Fan, Guangjin, Lou, Linlin, Wang, Yuanxiang, Zhang, Xiaolei, Xiong, Xiao-Feng
Format: Article
Language:English
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Summary:[Display omitted] •Discovery of novel indazole-scaffold derivatives as SOS1 agonists.•Compound 11 displayed high activation potency on active RAS-GTP and ERK1/2 phosphorylation via a SOS1 dependent on-target mechanism.•These findings highlight an “activity cliff” example by a marginal structural modification. KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC50 = 1.53 μM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2023.117457