TY - JOUR
T1 - Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis
AU - Smith, Alasdair
AU - Wall, Richard J.
AU - Patterson, Stephen
AU - Rowan, Tim
AU - Rico Vidal, Eva
AU - Stojanovski, Laste
AU - Huggett, Margaret
AU - Hampton, Shahienaz E.
AU - Thomas, Michael G.
AU - Corpas Lopez, Victoriano
AU - Gillingwater, Kirsten
AU - Duke, Jeff
AU - Napier, Grant
AU - Peter, Rose
AU - Vitouley, Hervé S.
AU - Harrison, Justin R.
AU - Milne, Rachel
AU - Jeacock, Laura
AU - Baker, Nicola
AU - Davis, Susan H.
AU - Simeons, Frederick
AU - Riley, Jennifer
AU - Horn, David
AU - Brun, Reto
AU - Zuccotto, Fabio
AU - Witty, Michael J.
AU - Wyllie, Susan
AU - Read, Kevin D.
AU - Gilbert, Ian H.
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127364726&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c02104
DO - 10.1021/acs.jmedchem.1c02104
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C2 - 35303411
AN - SCOPUS:85127364726
VL - 65
SP - 5606
EP - 5624
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -
