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

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

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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