Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1021/acs.jmedchem.5c00974

Type

Journal article

Journal

J Med Chem

Publication Date

06/08/2025