Comparative analysis of small-molecule limk1/2 inhibitors: chemical synthesis, biochemistry, and cellular activity

Collins, Ross, Lee, Hyunah, Jones, Dyfyr, Elkins, Jonathan M., Gillespie, Jason A., Thomas, Carys, Baldwin, Alex G. ORCID: https://orcid.org/0000-0002-7126-5220, Jones, Kimberley, Waters, Loren, Paine, Marie, Atack, John R. ORCID: https://orcid.org/0000-0002-3410-791X, Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377, Grubisha, Olivera ORCID: https://orcid.org/0000-0003-1067-1230 and Foley, David W. ORCID: https://orcid.org/0000-0001-8449-4754 2022. Comparative analysis of small-molecule limk1/2 inhibitors: chemical synthesis, biochemistry, and cellular activity. Journal of Medicinal Chemistry 10.1021/acs.jmedchem.2c00751

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	0022-2623
Funders:	MRC
Date of First Compliant Deposit:	24 October 2022
Date of Acceptance:	7 October 2022
Last Modified:	06 Jan 2024 03:11
URI:	https://orca.cardiff.ac.uk/id/eprint/153581

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