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Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

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Authors

  • Laura A. T. Cleghorn
  • Andrew Woodland
  • Iain T. Collie
  • Leah S. Torrie
  • Neil Norcross
  • Torsten Luksch
  • Chido Mpamhanga
  • Roderick G. Walker
  • Jeremy C. Mottram
  • Ruth Brenk
  • Julie A. Frearson
  • Ian H. Gilbert
  • Paul G. Wyatt (Lead / Corresponding author)

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Info

Original languageEnglish
Pages2214-2224
Number of pages11
JournalChemMedChem
Journal publication date9 Dec 2011
Volume6
Issue12
DOIs
StatePublished
Peer-reviewedYes

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 similar to 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.

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