X‐ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome

• DOI: 10.1002/cmdc.201800344
• Publication Date: 2018-07-09T13:55:07Z
• Authors: Joerg Kallen; Christian Bergsdorf; Bertrand Arnaud; Mario Bernhard; Murielle Brichet; Amanda Cobos‐Correa; Azeddine Elhajouji; Felix Freuler; Ivan Galimberti; Christel Guibourd...; Simon Haenni; Sandra Holzinger; Juerg Hunziker; Aude Izaac; Markus Kaufmann; Lukas Leder; Hans‐Joerg Martus; Peter von Matt; Valery Polyakov; Patrik Roethlisbe...; Guglielmo Roma; Nikolaus Stiefl; Marianne Uteng; Andreas Lerchner
• Keywords: Indazole

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of very potent indazole CLK inhibitor series X-ray structure most analogue are reported. This new was identified through biochemical Caliper assay screen with 30k compounds selected by an silico approach. Novel high-resolution structures all CLKs, including first CLK4 structure, bound known tool (e.g., TG003, CX-4945), also shown yield insight into selectivity family. The efficacy inhibitors from demonstrated mouse brain slice assay, safety concerns were investigated. Genotoxicity findings human lymphocyte micronucleus test (MNT) using two structurally different reveal major concern for pan-CLK PMDS.