title: Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases.
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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Woodard
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: April K
authors.initials: AK
authors.lastname: Kathcart
authors.forename: James
authors.initials: J
authors.lastname: Terrell
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Miriam
authors.initials: M
authors.lastname: Lopez-Sanchez
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nichols
authors.forename: William
authors.initials: W
authors.lastname: Ellis
authors.forename: Sean T
authors.initials: ST
authors.lastname: Prigge
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Geyer
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D007211:Indoles; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase