AI Article Synopsis
- LIMKs are key regulators of actin and microtubule dynamics, crucial for various cellular functions, and their deregulation is linked to diseases like cancer and cognitive disorders.
- Researchers have developed three selective inhibitors for LIMK1/2 that demonstrate low nanomolar affinity and strong selectivity across all binding types (I, II, III).
- These inhibitors show distinct effects in phosphoproteomics and promising activity in models for fragile X syndrome, indicating potential for treating this condition.
Article Abstract
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 (; type I), (; type II), and (; 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 . In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675044 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.2c01106 | DOI Listing |
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