Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome

TY - JOUR

T1 - Discovery of MDI-114215

T2 - A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome

AU - Baldwin, Alex G

AU - Foley, David W

AU - Collins, Ross

AU - Lee, Hyunah

AU - Jones, D Heulyn

AU - Wahab, Ben

AU - Waters, Loren

AU - Pedder, Josephine

AU - Paine, Marie

AU - Feng, Gui Jie

AU - Privitera, Lucia

AU - Ashall-Kelly, Alexander

AU - Thomas, Carys

AU - Gillespie, Jason A

AU - Schino, Lauramariú

AU - Belelli, Delia

AU - Rocha, Cecilia

AU - Maussion, Gilles

AU - Krahn, Andrea I

AU - Durcan, Thomas M

AU - Elkins, Jonathan M

AU - Lambert, Jeremy J

AU - Atack, John R

AU - Ward, Simon E

N1 - Copyright © 2024 The Authors.

PY - 2025/1/9

Y1 - 2025/1/9

N2 - 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.

AB - 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.

KW - Lim Kinases/antagonists & inhibitors

KW - Fragile X Syndrome/drug therapy

KW - Animals

KW - Humans

KW - Mice

KW - Protein Kinase Inhibitors/pharmacology

KW - Drug Discovery

KW - Structure-Activity Relationship

KW - Induced Pluripotent Stem Cells/metabolism

KW - Long-Term Potentiation/drug effects

KW - Hippocampus/drug effects

KW - Neurons/drug effects

KW - Actin Depolymerizing Factors/metabolism

KW - Male

KW - Mice, Inbred C57BL

UR - https://www.scopus.com/pages/publications/85212791666

U2 - 10.1021/acs.jmedchem.4c02694

DO - 10.1021/acs.jmedchem.4c02694

M3 - Article

C2 - 39711116

SN - 0022-2623

VL - 68

SP - 719

EP - 752

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -