Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes

被引：15

作者：

Hanke, Thomas ^{[1
,2
]}

Mathea, Sebastian ^{[1
,2
]}

Woortman, Julia ^{[3
]}

Salah, Eidarus ^{[4
]}

Berger, Benedict-Tilman ^{[1
,2
]}

Tumber, Anthony ^{[4
]}

Kashima, Risa ^{[5
]}

Hata, Akiko ^{[5
]}

Kuster, Bernhard ^{[3
,6
]}

Mueller, Susanne ^{[1
,2
]}

Knapp, Stefan ^{[1
,2
]}

机构：

[1] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt, Germany

[2] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium SGC, D-60438 Frankfurt, Germany

[3] Tech Univ Munich TUM, Chair Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany

[4] Univ Oxford, Chem Res Lab, Oxford OX1 3TA, England

[5] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA

[6] German Translat Canc Network DKTK, Site Frankfurt Mainz, German Canc Res Ctr DKFZ, D-69120 Heidelberg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 19期

关键词：

ACTIVATION; INHIBITOR; PROTEINS; RECEPTOR; BINDING; IDENTIFICATION; DISCOVERY; DESIGN;

D O I：

10.1021/acs.jmedchem.2c01106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.

引用

页码：13264 / 13287

页数：24

共 45 条

[1] Trends in kinase drug discovery: targets, indications and inhibitor design [J].