The discovery of kinase inhibitors by a combination of diversity-oriented synthesis and selective screening

Jinbao Xiang, Zhuoqi Zhang, Renzhong Fu, Robert J. Ternansky, Patricia L. Gladstone, Amy L. Allan, Fernando Donate, Graham Parry, Jose Juarez, Andrew P. Mazar, Xu Bai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

An efficient strategy for the discovery of kinase inhibitors by a combination of diversity-oriented synthesis and selective screening is described. Initially, a set of 10 compounds representing a 10-scaffold library of diversity-oriented pyrimidine-containing compounds were tested against 40 enzymes selected from the kinase family, which resulted in the discovery of a selective p38α inhibitor. In the next step, the subset from the scaffold with the active was screened against the pairing enzyme (p38α). Eventually, the most potent compounds were measured for IC50 (42.7 nM) and tested in MM1S and U266 cells by observing the complete suppression of the phosphorylation of p38α at submicromolar concentrations. Therefore, a series of novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines with potent inhibitory activity against p38α kinase in vitro and in cellular assays were discovered utilizing this methodology. This strategy may be applicable for the drug discovery of a superfamily of targets using a large library of compounds.

Original languageEnglish (US)
Pages (from-to)1946-1951
Number of pages6
JournalMedChemComm
Volume7
Issue number10
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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