2. Academic Validation
  3. Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis

Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis

  • J Med Chem. 2022 Apr 14;65(7):5606-5624. doi: 10.1021/acs.jmedchem.1c02104.
Alasdair Smith 1,  Richard J Wall 2,  Stephen Patterson 2,  Tim Rowan 3,  Eva Rico Vidal 2,  Laste Stojanovski 1,  Margaret Huggett 1,  Shahienaz E Hampton 1,  Michael G Thomas 1,  Victoriano Corpas Lopez 2,  Kirsten Gillingwater 4 5,  Jeff Duke 6,  Grant Napier 3,  Rose Peter 3,  Hervé S Vitouley 7,  Justin R Harrison 1,  Rachel Milne 2,  Laura Jeacock 2,  Nicola Baker 2,  Susan H Davis 1,  Frederick Simeons 1,  Jennifer Riley 1,  David Horn 2,  Reto Brun 4 5,  Fabio Zuccotto 1,  Michael J Witty 3,  Susan Wyllie 2,  Kevin D Read 1,  Ian H Gilbert 1
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
  • 2 Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
  • 3 GALVmed, Doherty Building, Pentlands Science Park, Bush Loan, Penicuik, Edinburgh EH26 0PZ, United Kingdom.
  • 4 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland.
  • 5 University of Basel, Petersplatz 1, CH-4001 Basel, Switzerland.
  • 6 University of Greenwich, Medway Campus, Central Avenue, Chatham Maritime, Chatham, Kent ME4 4TB United Kingdom.
  • 7 Centre International de Recherche-Développement sur l'Elevage en zone Subhumide (CIRDES), No 559 ru 5-31 angle Av. du Gouverneur Louveau, 01 BP: 454 Bobo-Dioulasso 01, Burkina Faso.
PMID: 35303411 DOI: 10.1021/acs.jmedchem.1c02104
Abstract

African animal trypanosomiasis or nagana, caused principally by Infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.

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