药效团
化学
克拉斯
计算生物学
突变体
肽
结合位点
小分子
生物化学
组合化学
突变
基因
生物
作者
Gabriele Fumagalli,Rodrigo J. Carbajo,J. Willem M. Nissink,Jonathan Tart,Rongxuan Dou,Andrew P. Thomas,David R. Spring
标识
DOI:10.1021/acs.jmedchem.1c01334
摘要
RAS proteins are central in the proliferation of many types of cancer, but a general approach toward the identification of pan-mutant RAS inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known RAS binding peptides to the design of novel peptides. Using a chemically divergent approach, we generated a library of small stapled peptides from which we identified compounds with weak binding activity. Exploration of structure-activity relationships (SARs) and optimization of these early compounds led to low-micromolar binders of KRAS that block nucleotide exchange.
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