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| Home > Publications database > Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader. |
| Home > Publications database > Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader. |
| Journal Article | DKFZ-2026-01039 |
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2026
Soc.
Washington, DC
Abstract: The LIM kinases (LIMK1/2) are key mediators in signaling cascades that regulate actin cytoskeleton dynamics via cofilin phosphorylation. Dysregulation of these pathways and overexpression of LIMKs are implicated in disease development, including cancer, Fragile X syndrome, and glaucoma. Positioned downstream of actin-regulating Rho GTPase signaling pathways, LIM kinases are attractive drug targets. Here, we targeted LIMKs with PROTACs to disrupt both catalytically and noncatalytically mediated functions. Despite employing a dual LIMK1/2 inhibitor warhead and high structural conservation between the two human LIM kinases, we discovered isoform-specific LIMK2 degradation by initial PROTACs that we optimized into a highly potent and selective LIMK2 degrader. Cell-based assays and structural analysis indicated that isoform specificity was likely driven by favorable orientation bias and/or lysine accessibility, along with enhanced ternary complex formation. We comprehensively characterized the PROTAC as a chemical probe that induces isoform-specific degradation, offering a powerful alternative to conventional reversible pan-LIMK inhibitors.
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