Abbott Jason R, Patel Pratiq A, Howes Jennifer E, Akan Denis T, Kennedy J Phillip, Burns Michael C, Browning Carrie F, Sun Qi, Rossanese Olivia W, Phan Jason, Waterson Alex G, Fesik Stephen W
Department of Biochemistry and Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232-0146, United States.
ACS Med Chem Lett. 2018 Aug 8;9(9):941-946. doi: 10.1021/acsmedchemlett.8b00296. eCollection 2018 Sep 13.
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.
RAS家族中的蛋白质是细胞信号传导的重要调节因子，发生突变时可推动癌症发病机制。尽管在过去30年中付出了巨大努力，但RAS蛋白已被证明是难以攻克的治疗靶点。调节RAS信号传导的一种方法是靶向与RAS相互作用的蛋白质，例如鸟嘌呤核苷酸交换因子（GEF）七号less同源物1（SOS1）。在此，我们报告了对与SOS1结合并激活RAS上核苷酸交换的含喹唑啉化合物的从苗头化合物到先导化合物的研究。利用基于结构的设计，我们优化了连接在喹唑啉核上的取代基，并引入了最初高通量筛选命中化合物中不存在的额外相互作用。优化后的化合物在体外以个位数微摩尔浓度激活核苷酸交换。在HeLa细胞中，这些喹唑啉增加了RAS-GTP的水平，并导致丝裂原活化蛋白激酶/细胞外调节激酶（MAPK/ERK）途径中的信号变化。
