Why the study?
Deregulation of LIMKs has been linked to diverse diseases including cancers and cognitive disabilities, but well-characterized chemical probe inhibitors were still lacking.
The development of highly selective LIMK1/2 inhibitors provides valuable chemical probes for studying LIMK biology and suggests potential therapeutic applications for fragile X-chromosome.
LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 ( LIMKi3; type I), 48 ( TH470; type II), and 15 ( TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15 . In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.
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Hanke et al. (2022) studied Fragile X-chromosome. LIMK1/2 inhibitors (LIMKi3, TH470, TH257) was evaluated on Kinase selectivity, phosphoproteomics, and phenotypic activity.
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