Discovery of novel 7-azaindoles as PDK1 inhibitors

被引：19

作者：

Wucherer-Plietker, Margarita ^{[1
]}

Merkul, Eugen ^{[2
,3
]}

Mueller, Thomas J. J. ^{[2
,3
]}

Esdar, Christina ^{[1
]}

Knoechel, Thorsten ^{[1
]}

Heinrich, Timo ^{[1
]}

Buchstaller, Hans-Peter ^{[1
]}

Greiner, Hartmut ^{[1
]}

Dorsch, Dieter ^{[1
]}

Finsinger, Dirk ^{[1
]}

Calderini, Michel ^{[1
]}

Bruge, David ^{[1
]}

Graedler, Ulrich ^{[1
]}

机构：

[1] Merck KGaA, Biopharma Global Res & Dev, Frankfurter Str 250, D-64293 Darmstadt, Germany

[2] Heidelberg Univ, Organ Chem Inst, Neuenheimer Feld 270, D-69120 Heidelberg, Germany

[3] Univ Dusseldorf, Inst Organ Chem & Makromol Chem, Univ Str 1, D-40225 Dusseldorf, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 13期

关键词：

PDK1; Kinase inhibitor; Structure-based design; Fragment-screening; Protein crystallography; Virtual screening; SMALL-MOLECULE INHIBITORS; KINASE INHIBITORS; POTENT; SELECTIVITY; MERIOLINS; PROTEIN;

D O I：

10.1016/j.bmcl.2016.05.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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 IC(50)s (e.g., 16: IC50 = 1.1 mu M) 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 mu M) 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. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：3073 / 3080

页数：8

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