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Novel CLK1 Inhibitors Based on N-aryloxazol-2-amine Skeleton - A Possible Way to Dual VEGFR2 TK/CLK Ligands

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Novel CLK1 Inhibitors Based on N-aryloxazol-2-amine Skeleton - A Possible Way to Dual VEGFR2 TK/CLK Ligands

Miroslav Murár et al. Eur J Med Chem.

Abstract

Background: Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics.

Achievements: Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2-amine skeleton. Their activity against CLK1 (IC50: 20, 30, 40 and 80 nM) and some other CMGC kinases, predicted CLK binding poses, synthesis and physico-chemical characteristics are also stated. Additionally analysis of all PDB available CLK structures and interactions of their ligands was performed. There are only few powerful dual CLK/VEGFR inhibitors known in the literature. We proposed that our inhibitors have similar binding places and interactions in CLK1, 3 and VEGFR2 TK mostly due to the joint N-aryloxazol-2-amine pharmacophoric fragment. One of our N-aryloxazol-2-amines already proved a good activity against both VEGFR2 and CLK1 enzymes (23/80 nM, resp). We proposed that the presented class of compounds has a potential to be developed in dual VEGFR2/CLK clinical compounds with prospective synergy to treat cancer.

Keywords: CDK9; DYRK1A; Dual CLK1/VEGFR2 kinase ligands; GSK3; GSK3α/β; IPHOJHHAZPKUQW-UHFFFAOYSA-N; Muti-targeted kinase inhibitors; XQSZOOXIJIGDLV-UHFFFAOYSA-N; YIEXHVPVWYOPCC-MDZDMXLPSA-N; ZIKVYDDNZDVYHF-UHFFFAOYSA-N.

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