Author: Elkins, Jonathan M. ; Thomas, Carys ; Collins, Ross ; Ward, Simon E. ; Waters, Loren ; Foley, David W. ; Jones, Kimberley ; Gillespie, Jason A. ; Jones, D. Heulyn ; Paine, Marie ; Atack, John R. ; Lee, Hyunah ; Grubisha, Olivera ; Baldwin, Alex G.

LIM domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics and subsequently key cellular functions such as proliferation and migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading to increased actin polymerization. As a result, LIMK inhibitors are emerging as a promising treatment strategy for certain cancers and neurological disorders. High-quality chemical probes are required if the role of these kinases in health and disease is to be understood. To that end, we report the results of a comparative assessment of 17 reported LIMK1/2 inhibitors in a variety of in vitro enzymatic and cellular assays. Our evaluation has identified three compounds (TH-257, LIJTF500025, and LIMKi3) as potent and selective inhibitors suitable for use as in vitro and in vivo pharmacological tools for the study of LIMK function in cell biology.

13 Oct 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Mathea, Sebastian ; Kashima, Risa ; Knapp, Stefan ; Salah, Eidarus ; Woortman, Julia ; Tumber, Anthony ; Hanke, Thomas ; Berger, Benedict-Tilman ; Kuster, Bernhard ; Hata, Akiko ; Müller, Susanne

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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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	GB	University of Cardiff	-

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