Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases

Cassandra L. Woodard, Zhiyu Li, April K. Kathcart, James Terrell, Lucia Gerena, Miriam Lopez-Sanchez, Dennis E. Kyle, Apurba K. Bhattacharjee, Daniel A. Nichols, William Ellis, Sean T. Prigge, Jeanne A. Geyer, Norman C. Waters

Research output: Contribution to journalArticle

Abstract

Cyclin dependent protein kinases (CDKs) have become attractive drug targets in an effort to identify effective inhibitors of the parasite Plasmodium falciparum, the causative agent of the most severe form of human malaria. We tested known CDK inhibitors for their ability to inhibit two malarial CDKs: Pfmrk and PfPK5. Many broad spectrum CDK inhibitors failed to inhibit Pfmrk suggesting that the active site differs from other CDKs in important ways. By screening compounds in the Walter Reed chemical database, we identified oxindole-based compounds as effective inhibitors of Pfmrk (IC 50 = 1.5 μM). These compounds have low cross-reactivity against PfPK5 and human CDK1 demonstrating selectivity for Pfmrk. Amino acid comparison of the active sites of Pfmrk and PfPK5 identified unique amino acid differences that may explain this selectivity and be exploited for further drug development efforts.

Original languageEnglish (US)
Pages (from-to)3877-3882
Number of pages6
JournalJournal of medicinal chemistry
Volume46
Issue number18
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Woodard, C. L., Li, Z., Kathcart, A. K., Terrell, J., Gerena, L., Lopez-Sanchez, M., Kyle, D. E., Bhattacharjee, A. K., Nichols, D. A., Ellis, W., Prigge, S. T., Geyer, J. A., & Waters, N. C. (2003). Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. Journal of medicinal chemistry, 46(18), 3877-3882. https://doi.org/10.1021/jm0300983