Discovery of MDI-114215: A potent and selective LIMK inhibitor to treat Fragile X Syndrome

Baldwin, Alex ORCID: https://orcid.org/0000-0002-7126-5220, Foley, David, Collins, Ross, Lee, Hyunah, Jones, D. Heulyn, Wahab, Ben, Waters, Loren, Pedder, Josephine, Paine, Marie, Feng, Gui, Privitera, Lucia, Ashall-Kelly, Alexander, Thomas, Carys, Gillespie, Jason, Schino, Lauramariu, Belelli, Delia, Rocha, Cecilia, Maussion, Gilles, Krahn, Andrea, Durcan, Thomas, Elkins, Jonathan, Lambert, Jeremy, Atack, John ORCID: https://orcid.org/0000-0002-3410-791X and Ward, Simon 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 kinasesresponsible for controlling cytoskeletal dynamics as key regulatorsof actin stability, ensuring synaptic health through normal synapticbouton structure and function. However, LIMK1 overactivationresults in abnormal dendritic synaptic development that character-izes the pathogenesis of Fragile X Syndrome (FXS). As a result, thedevelopment of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS. We report the discoveryof MDI-114215 (85), a novel, potent allosteric dual-LIMK1/2inhibitor that demonstrates exquisite kinome selectivity. 85 reducesphospho-cofilin in mouse brain slices and rescues impairedhippocampal long-term potentiation in brain slices from FXSmice. We also show that LIMK inhibitors are effective in reducingphospho-cofilin levels in iPSC neurons derived from FXS patients, demonstrating 85 to be a potential therapeutic candidate for FXSthat 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:	Chemistry Medicine Biosciences Medicines Discovery Institute (MDI)
Publisher:	American Chemical Society
Date of First Compliant Deposit:	9 January 2025
Date of Acceptance:	4 December 2024
Last Modified:	29 Jan 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/175133

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