广告
化学
IC50型
虚拟筛选
效力
结构-活动关系
配体效率
药理学
铅化合物
药物发现
计算生物学
生物化学
组合化学
体外
配体(生物化学)
受体
医学
生物
作者
Margarita Wucherer-Plietker,Eugen Merkul,Thomas J. J. Müller,Christina Esdar,Thorsten Knöchel,Timo Heinrich,Hans‐Peter Buchstaller,Hartmut E. Greiner,Dieter Dorsch,Dirk Finsinger,Michel Calderini,David Bruge,Ulrich Grädler
标识
DOI:10.1016/j.bmcl.2016.05.005
摘要
A combined screening strategy using HTS together with focused kinase library and virtual screening led to the identification of diverse chemical series as PDK1 inhibitors. We focused our medicinal chemistry efforts on 7-azaindoles with low micromolar IC50s (e.g., 16: IC50 = 1.1 μM) in the biochemical PDK1 assay. Our structure-guided optimization efforts considered also PDK1 X-ray structures with weaker binding fragments and resulted in 7-azaindoles with significantly improved biochemical PDK1 potency in the two-digit nanomolar range. However, the most potent analogues only showed moderate activities in a cellular mechanistic assay (42: IC50 = 2.3 μM) together with either low microsomal stability or low permeability. The described structure–activity relationship together with PDK1 X-ray structures and early ADME data provided the basis for our subsequent hit-to-lead program.
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