Tetrahydropyrazolopyridinones as a novel class of potent and highly selective LIMK inhibitors

Baldwin, Alex ORCID: https://orcid.org/0000-0002-7126-5220, Foley, David W., Jones, Heulyn, Lee, Hyunah, Collins, Ross, Wahab, Ben, Pedder, Josephine, Waters, Loren, Paine, Marie, Schino, Lauramariu, Feng, Gui, Kariuki, Benson ORCID: https://orcid.org/0000-0002-8658-3897, Elkins, Jonathan M., Atack, John ORCID: https://orcid.org/0000-0002-3410-791X and Ward, Simon ORCID: https://orcid.org/0000-0002-8745-8377 2025. Tetrahydropyrazolopyridinones as a novel class of potent and highly selective LIMK inhibitors. Journal of Medicinal Chemistry 10.1021/acs.jmedchem.5c00974

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Abstract

LIMKs are serine/threonine and tyrosine kinases that play critical roles in regulating actin filament turnover, affecting key cellular processes such as cytoskeletal remodeling, proliferation and migration. Aberrant LIMK overactivation has been implicated in several diseases, including cancers and neurodegenerative disorders. Understanding the precise molecular mechanisms by which LIMKs modulate actin cytoskeletal dynamics necessitates highly potent and selective LIMK pharmacological inhibitors. We report the discovery of a novel class of allosteric dual-LIMK1/2 inhibitors based on the tetrahydropyrazolopyridinone scaffold. Using structure-based drug design, we identified MDI-117740 (69) as a highly potent dual-LIMK1/2 inhibitor with significantly improved DMPK properties compared to prior inhibitors, suitable for in vivo evaluation. Importantly, 69 has very low kinome promiscuity, including former off-target RIPK1, representing the most selective LIMK inhibitor reported to date. Such a chemical probe will enable researchers to selectively dissect LIMK activation under physiological or disease conditions and spur translation of new therapeutics targeting LIMK pathologies.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences Research Institutes & Centres > Medicines Discovery Institute (MDI)
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	6 August 2025
Date of Acceptance:	23 July 2025
Last Modified:	06 Aug 2025 10:48
URI:	https://orca.cardiff.ac.uk/id/eprint/180286

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