- Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands
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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.
- Murár, Miroslav,Dobia?, Juraj,?ramel, Peter,Addová, Gabriela,Hanquet, Gilles,Bohá?, Andrej
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supporting information
p. 754 - 761
(2016/12/16)
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- Synthesis of highly potent and selective hetaryl ureas as integrin αVβ3-receptor antagonists
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Solid-phase synthesis and SAR of integrin αVβ3-receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC50 values towards αVβ3 in the nanomolar range and high selectivity versus related integrins like αIIbβ3. For selected examples efficacy in functional cellular assays is demonstrated.
- Lange, Udo E.W.,Backfisch, Gisela,Delzer, Juergen,Geneste, Herve,Graef, Claudia,Hornberger, Wilfried,Kling, Andreas,Lauterbach, Arnulf,Subkowski, Thomas,Zechel, Christian
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p. 1379 - 1382
(2007/10/03)
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