Comparative Analysis of Small-Molecule LIMK1/2 Inhibitors: Chemical Synthesis, Biochemistry, and Cellular Activity

  • J Med Chem. 2022 Oct 27;65(20):13705-13713. doi: 10.1021/acs.jmedchem.2c00751.
Ross Collins  1 ,  Hyunah Lee  2 ,  D Heulyn Jones  1 ,  Jonathan M Elkins  2 ,  Jason A Gillespie  1 ,  Carys Thomas  1 ,  Alex G Baldwin  1 ,  Kimberley Jones  1 ,  Loren Waters  1 ,  Marie Paine  1 ,  John R Atack  1 ,  Simon E Ward  1 ,  Olivera Grubisha  1 ,  David W Foley  1
Affiliations
  • 1. Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff CF10 3AT, United Kingdom.
  • 2. Centre for Medicines Discovery, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
PMID: 36205722 DOI: 10.1021/acs.jmedchem.2c00751
Abstract

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.

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