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

Alasdair Smith, Richard J. Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz E. Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rose Peter, Hervé S. Vitouley, Justin R. Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan H. DavisFrederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie, Kevin D. Read, Ian H. Gilbert

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)5606-5624
Number of pages19
JournalJournal of Medicinal Chemistry
Volume65
Issue number7
DOIs
StatePublished - 14 Apr 2022
Externally publishedYes

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