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
  • 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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