title: Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.
abstract: BACKGROUND
  Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT.
  
  
  RESULTS
  A subset of over 16,000 inhibitors of HsGSK-3 β from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed.
  
  
  CONCLUSIONS
  We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds.
authors.affiliation: Opportunities for Partnering in Medicine, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Oduor
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.forename: Gareth P
authors.initials: GP
authors.lastname: Williams
authors.forename: Francois
authors.initials: F
authors.lastname: Bertelli
authors.forename: James
authors.initials: J
authors.lastname: Mills
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
authors.forename: Tanya
authors.initials: T
authors.lastname: Parkinson
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Tod P
authors.initials: TP
authors.lastname: Holler
mesh_terms: D000981:Antiprotozoal Agents / Q000302:isolation & purification* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D017434:Protein Structure, Tertiary; D055818:Public-Private Sector Partnerships; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3