Tetrahydropyrazolopyridinones as a Novel Class of Potent and Highly Selective LIMK Inhibitors

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.