Novel, selective CDK9 inhibitors for the treatment of HIV infection

G. Németh, Z. Varga, Z. Greff, G. Bencze, A. Sipos, C. Szántai-Kis, F. Baska, Á Gyuris, K. Kelemenics, Z. Szathmáry, J. Minárovits, G. Kéri, L. Orfi

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-todate review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC50 < 100nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.

Original languageEnglish (US)
Pages (from-to)342-358
Number of pages17
JournalCurrent medicinal chemistry
Volume18
Issue number3
DOIs
StatePublished - Jan 2011

Keywords

  • 4-aminophenyl-6-phenyl-pyrimidine
  • CDK9
  • HIV
  • Intermediate
  • Kinase inhibitor
  • Selectivity
  • Synthesis

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