Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome
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 (<b>85</b>), a novel, potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite kinome selectivity. <b>85</b> 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 <b>85</b> 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.
Authors
- Andrea I. Krahn (ORCID: https://orcid.org/0000-0002-7975-6489)
- Carys Thomas
- Cecilia Rocha
- Jason A. Gillespie
- Thomas M. Durcan (ORCID: https://orcid.org/0000-0003-3942-1956)
- Gilles Maussion (ORCID: https://orcid.org/0000-0001-5785-6238)
- Delia Belelli (ORCID: https://orcid.org/0000-0001-7912-8637)
- John Atack
- D. Heulyn Jones (ORCID: https://orcid.org/0000-0002-4290-2999)
- Alex G. Baldwin (ORCID: https://orcid.org/0000-0002-7126-5220)
- Ross J. Collins (ORCID: https://orcid.org/0000-0002-5759-7659)
- Jonathan M. Elkins (ORCID: https://orcid.org/0000-0003-2858-8929)
- Simon E. Ward (ORCID: https://orcid.org/0000-0002-8745-8377)
- Ben Wahab
- Loren Waters
- Marie Paine
- Alexander Ashall-Kelly
- Hyun-Ah Lee (ORCID: https://orcid.org/0000-0002-2294-6695)
- David Foley
- Lucia Privitera (ORCID: https://orcid.org/0000-0002-3280-8026)
- Jeremy J. Lambert (ORCID: https://orcid.org/0000-0002-4204-3602)
- Gui Jie Feng (ORCID: https://orcid.org/0000-0002-6145-8504)
- Jonathan Pedder
- Lauramariú Schino
Institutions
- Montreal Neurological Institute and Hospital (CA)
- University of Dundee (GB)
- University of Oxford (GB)
- McGill University (CA)
- Cardiff University (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02694
- Citations
- 7
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.85
Funders
- Medical Research Council