title: Identification of inhibitors of the Leishmania cdc2-related protein kinase CRK3.
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.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodland
authors.forename: Iain T
authors.initials: IT
authors.lastname: Collie
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.forename: Neil
authors.initials: N
authors.lastname: Norcross
authors.forename: Torsten
authors.initials: T
authors.lastname: Luksch
authors.forename: Chido
authors.initials: C
authors.lastname: Mpamhanga
authors.forename: Roderick G
authors.initials: RG
authors.lastname: Walker
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology; D007896:Leishmaniasis / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011720:Pyrazoles; D011743:Pyrimidines; C031280:pyrazole; D014508:Urea; D016203:CDC2 Protein Kinase; C030986:pyrimidine