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Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors.

Abstract：

:Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-ß, c-Kit, c-Met, Src, Raf, VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6 nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4-anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Ravez S,Arsenlis S,Barczyk A,Dupont A,Frédérick R,Hesse S,Kirsch G,Depreux P,Goossens L

doi

10.1016/j.bmc.2015.10.035

subject

Has Abstract

pub_date

2015-11-15 00:00:00

pages

7340-7

issue

22

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)30113-9

journal_volume

23

pub_type

杂志文章

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