Format

Send to

Choose Destination
Eur J Med Chem. 2017 Jan 27;126:754-761. doi: 10.1016/j.ejmech.2016.11.003. Epub 2016 Nov 18.

Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands.

Author information

1
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
2
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia; Université de Strasbourg, Ecole Européenne de Chimie, Polyméres et Matériaux (ECPM) Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, Rue Becquerel, F-67087 Strasbourg, France.
3
Institute of Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
4
Université de Strasbourg, Ecole Européenne de Chimie, Polyméres et Matériaux (ECPM) Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, Rue Becquerel, F-67087 Strasbourg, France.
5
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia; Biomagi, Ltd., Mamateyova 26, 851 04 Bratislava, Slovakia. Electronic address: andrej.bohac@fns.uniba.sk.

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

PMID:
27940419
DOI:
10.1016/j.ejmech.2016.11.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center