Structure-based design of PDK1 inhibitors

被引：11

作者：

Poulsen, Anders ^{[1
]}

Blanchard, Stephanie ^{[1
]}

Soh, Chang Kai ^{[1
]}

Lee, Chaiping ^{[1
]}

Williams, Meredith ^{[1
]}

Wang, Haishan ^{[1
]}

Dymock, Brian ^{[1
]}

机构：

[1] S BIO Pte Ltd, Singapore 117528, Singapore

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 01期

关键词：

3-Phosphoinositide-dependent kinase 1 (PDK1); Structure-based design; Selectivity; Inhibitor; 4-Aryl-purine; DISCOVERY; POTENT;

D O I：

10.1016/j.bmcl.2011.11.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A macrocyclic 2-anilino-4-phenyl-pyrimidine CDK/Flt3/JAK2 inhibitor was found to have moderate PDK1 activity. After docking into a PDK1 X-ray structure it was suggested that the pyrimidine ring could be substituted for a purine thereby increasing the number of hydrophobic contacts with the protein and forming an additional hydrogen bond to the kinase hinge. Deletion of the macrocyclic linker allowed a more rapid optimisation of the aromatic substituents as well as the introduction of an amino-amide solubility tag. This improved both binding to the enzyme and physiochemical properties without compromising ligand efficiency. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：305 / 307

页数：3

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