Document Report Card

ID: ALA1145071

Journal: J Med Chem

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

Authors: Woodard CL, Li Z, Kathcart AK, Terrell J, Gerena L, Lopez-Sanchez M, Kyle DE, Bhattacharjee AK, Nichols DA, Ellis W, Prigge ST, Geyer JA, Waters NC.

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 microM). 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.

CiteXplore: 12930149

DOI: 10.1021/jm0300983