Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases.
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.
Woodard
Cassandra L
CL
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
Li
Zhiyu
Z
Kathcart
April K
AK
Terrell
James
J
Gerena
Lucia
L
Lopez-Sanchez
Miriam
M
Kyle
Dennis E
DE
Bhattacharjee
Apurba K
AK
Nichols
Daniel A
DA
Ellis
William
W
Prigge
Sean T
ST
Geyer
Jeanne A
JA
Waters
Norman C
NC
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
D000962:Antimalarials; D004791:Enzyme Inhibitors; D007211:Indoles; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase