Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9.

Journal Article (Journal Article)

Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization.

Full Text

Duke Authors

Cited Authors

  • Gao, J; Fang, C; Xiao, Z; Huang, L; Chen, C-H; Wang, L-T; Lee, K-H

Published Date

  • March 1, 2015

Published In

Volume / Issue

  • 6 / 3

Start / End Page

  • 444 - 454

PubMed ID

  • 25914804

Pubmed Central ID

  • PMC4406325

International Standard Serial Number (ISSN)

  • 2040-2503

Digital Object Identifier (DOI)

  • 10.1039/C4MD00412D


  • eng

Conference Location

  • England