Tetrahydropyrazolopyridinones as a Novel Class of Potent and Highly Selective LIMK Inhibitors.
Baldwin AG., Foley DW., Jones DH., Lee H., Collins R., Wahab B., Pedder JH., Waters L., Paine M., Schino L., Feng GJ., Kariuki BM., Elkins JM., Atack JR., Ward SE.
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.