Abstract
New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Binding Sites
-
CDC2 Protein Kinase / antagonists & inhibitors*
-
CDC2 Protein Kinase / metabolism
-
Computer Simulation
-
Drug Evaluation, Preclinical
-
Humans
-
Leishmania / drug effects*
-
Leishmania / enzymology
-
Leishmaniasis / drug therapy
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Kinase Inhibitors / therapeutic use
-
Protein Structure, Tertiary
-
Protozoan Proteins / antagonists & inhibitors*
-
Protozoan Proteins / metabolism
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology
-
Pyrazoles / therapeutic use
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology
-
Pyrimidines / therapeutic use
-
Structure-Activity Relationship
-
Urea / chemistry
-
Urea / pharmacology
-
Urea / therapeutic use
Substances
-
Protein Kinase Inhibitors
-
Protozoan Proteins
-
Pyrazoles
-
Pyrimidines
-
pyrazole
-
Urea
-
CDC2 Protein Kinase
-
pyrimidine