Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling,Journal of Medicinal Chemistry

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Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-01 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00360
Jason R Abbott , Timothy R Hodges , R Nathan Daniels , Pratiq A Patel , J Phillip Kennedy , Jennifer E Howes , Denis T Akan , Michael C Burns , Jiqing Sai , Tammy Sobolik , Yugandhar Beesetty , Taekyu Lee , Olivia W Rossanese , Jason Phan , Alex G Waterson ₁ , Stephen W Fesik ₁

Affiliation

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure–activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS–GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase−extracellular regulated kinase (MAPK–ERK) pathway, resulting in a decrease in pERK1/2^T202/Y204 protein levels at higher compound concentrations.

中文翻译：

发现可激活鸟嘌呤核苷酸交换因子 SOS1 并调节 RAS 信号转导的氨基哌啶吲哚

RAS 活性失调通常是突变的结果，约 30% 的人类癌症与此有关。尽管有这一统计数据，但尚未开发出针对 RAS 驱动肿瘤的临床成功治疗方法。调节 RAS 活性的一种方法是靶向并影响与 RAS 相互作用的蛋白质的活性，例如七同源物 1 (SOS1) 的鸟嘌呤核苷酸交换因子 (GEF)。在这里，我们报告了吲哚系列化合物的构效关系 (SAR)。使用基于结构的设计，我们系统地探索了吲哚核、悬垂氨基酸部分以及连接这两个片段的连接单元的取代模式。一流的化合物可在体外以亚微摩尔浓度激活核苷酸交换过程，提高 HeLa 细胞中活性 RAS-GTP 的水平，并引发丝裂原激活蛋白激酶 - 细胞外调节激酶 (MAPK-ERK) 通路中的信号传导变化，导致较高化合物浓度下 pERK1/2 ^T202/Y204蛋白水平降低。

更新日期：2018-06-01

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