X‐ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome |
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| Authors: | Dr Joerg Kallen Dr Christian Bergsdorf Bertrand Arnaud Mario Bernhard Murielle Brichet Dr Amanda Cobos‐Correa Dr Azeddine Elhajouji Felix Freuler Dr Ivan Galimberti Dr Christel Guibourdenche Simon Haenni Sandra Holzinger Dr Juerg Hunziker Aude Izaac Markus Kaufmann Dr Lukas Leder Dr Hans‐Joerg Martus Dr Peter von Matt Dr Valery Polyakov Patrik Roethlisberger Dr Guglielmo Roma Dr Nikolaus Stiefl Dr Marianne Uteng Dr Andreas Lerchner |
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| Affiliation: | 1. Novartis Institutes for BioMedical Research, Basel, Switzerland;2. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland |
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| Abstract: | CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan–McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X‐ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high‐resolution X‐ray structures of all CLKs, including the first CLK4 X‐ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX‐4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan‐CLK inhibition in PMDS. |
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| Keywords: | enzymes genotoxicity inhibitors medicinal chemistry X-ray diffraction |
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