Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor

被引：82

作者：

Karpov, Alexei S. ^{[1
]}

Amiri, Payman ^{[2
]}

Bellamacina, Cornelia ^{[2
]}

Bellance, Marie-Helene ^{[1
]}

Breitenstein, Werner ^{[1
]}

Daniel, Dylan ^{[2
]}

Denay, Regis ^{[1
]}

Fabbro, Doriano ^{[1
]}

Fernandez, Cesar ^{[1
]}

Galuba, Inga ^{[1
]}

Guerro-Lagasse, Stephanie ^{[1
]}

Gutmann, Sascha ^{[1
]}

Hinh, Linda ^{[2
]}

Jahnke, Wolfgang ^{[1
]}

Klopp, Julia ^{[1
]}

Lai, Albert ^{[2
]}

Lindvall, Mika K. ^{[2
]}

Ma, Sylvia ^{[2
]}

Moebitz, Henrik ^{[1
]}

Pecchi, Sabina ^{[2
]}

Rummel, Gabriele ^{[1
]}

Shoemaker, Kevin ^{[2
]}

Trappe, Joerg ^{[1
]}

Voliva, Charles ^{[2
]}

Cowan-Jacob, Sandra W. ^{[1
]}

Marzinzik, Andreas L. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4056 Basel, Switzerland

[2] Novartis Inst BioMed Res, Emeryville, CA 94608 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 07期

关键词：

PAK1; p21 activated kinase; allosteric inhibitor; dibenzodiazepine; tool compound; SMALL-MOLECULE INHIBITOR; FRAGILE-X-SYNDROME; P21-ACTIVATED KINASES; AUTOPHOSPHORYLATION; ACTIVATION; DISCOVERY; MECHANISM; CANCER; MICE;

D O I：

10.1021/acsmedchemlett.5b00102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.

引用

页码：776 / 781

页数：6

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