Discovery of MDI-114215: A potent and selective LIMK inhibitor to treat fragile X syndrome

Baldwin, Alex G. ORCID: https://orcid.org/0000-0002-7126-5220, Foley, David W. ORCID: https://orcid.org/0000-0001-8449-4754, Collins, Ross, Lee, Hyunah, Jones, D. Heulyn, Wahab, Ben, Waters, Loren, Pedder, Josephine, Paine, Marie, Feng, Gui Jie, Privitera, Lucia, Ashall-Kelly, Alexander, Thomas, Carys, Gillespie, Jason A., Schino, Lauramariú, Belelli, Delia, Rocha, Cecilia, Maussion, Gilles, Krahn, Andrea I., Durcan, Thomas M., Elkins, Jonathan M., Lambert, Jeremy J., Atack, John R. ORCID: https://orcid.org/0000-0002-3410-791X and Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377 2025. Discovery of MDI-114215: A potent and selective LIMK inhibitor to treat fragile X syndrome. Journal of Medicinal Chemistry 68 (1) , pp. 719-752. 10.1021/acs.jmedchem.4c02694

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Abstract

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS. We report the discovery of MDI-114215 (85), a novel, potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite kinome selectivity. 85 reduces phospho-cofilin in mouse brain slices and rescues impaired hippocampal long-term potentiation in brain slices from FXS mice. We also show that LIMK inhibitors are effective in reducing phospho-cofilin levels in iPSC neurons derived from FXS patients, demonstrating 85 to be a potential therapeutic candidate for FXS that could have broad application to neurological disorders or cancers caused by LIMK1/2 overactivation and actin instability.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	6 January 2025
Date of Acceptance:	4 December 2024
Last Modified:	09 Jan 2025 15:25
URI:	https://orca.cardiff.ac.uk/id/eprint/175044

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