2. Academic Validation
  3. Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes

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

  • J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106.
Thomas Hanke 1 2,  Sebastian Mathea 1 2,  Julia Woortman 3,  Eidarus Salah 4,  Benedict-Tilman Berger 1 2,  Anthony Tumber 4,  Risa Kashima 5,  Akiko Hata 5,  Bernhard Kuster 3 6,  Susanne Müller 1 2,  Stefan Knapp 1 2 6
Affiliations

Affiliations

  • 1 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
  • 3 Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), D-85354 Freising, Germany.
  • 4 Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
  • 5 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, United States.
  • 6 German Translational Cancer Network (DKTK), Site Frankfurt/Mainz, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
PMID: 36136092 DOI: 10.1021/acs.jmedchem.2c01106
Abstract

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.

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