6fyl
X-ray structure of CLK2-KD(136-496)/CX-4945 at 1.95A
Structural highlights
Function[CLK2_HUMAN] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.[1] [2] [3] [4] Publication Abstract from PubMedCLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, we report the discovery of a very potent indazole CLK inhibitor series, and the CLK2 X-ray structure of its most potent analog. This new indazole series was identified via a biochemical CLK2 Caliper assay screen with 30k compounds that were 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 insights into inhibitor selectivity in the CLK family. Efficacy of our new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. We show genotoxicity findings in the human lymphocyte MNT assay using two structurally different CLK inhibitors, which reveals a major concern for pan-CLK inhibition in PMDS. X-ray structures and feasibility assessment of CLK2 inhibitors for Phelan McDermid syndrome.,Lerchner AM, Kallen J, Bergsdorf C, Arnaud B, Bernhard M, Brichet M, Cobos-Correa A, Elhajouji A, Freuler F, Galimberti I, Guibourdenche C, Haenni S, Holzinger S, Hunziker J, Izaac A, Kaufmann M, Leder L, Martus HJ, von Matt P, Polyakov V, Roethlisberger P, Roma G, Stiefl N, Uteng M ChemMedChem. 2018 Jul 9. doi: 10.1002/cmdc.201800344. PMID:29985556[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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