Repositioning of
a Diaminothiazole Series Confirmed
to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment
of African Animal Trypanosomiasis
Posted on 2022-03-18 - 23:44
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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Smith, Alasdair; Wall, Richard J.; Patterson, Stephen; Rowan, Tim; Rico Vidal, Eva; Stojanovski, Laste; et al. (2022). Repositioning of
a Diaminothiazole Series Confirmed
to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment
of African Animal Trypanosomiasis. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.1c02104
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AUTHORS (29)
AS
Alasdair Smith
RW
Richard J. Wall
SP
Stephen Patterson
TR
Tim Rowan
ER
Eva Rico Vidal
LS
Laste Stojanovski
MH
Margaret Huggett
SH
Shahienaz E. Hampton
MT
Michael G. Thomas
VC
Victoriano Corpas Lopez
KG
Kirsten Gillingwater
JD
Jeff Duke
GN
Grant Napier
RP
Rose Peter
HV
Hervé S. Vitouley
JH
Justin R. Harrison
RM
Rachel Milne
LJ
Laura Jeacock
NB
Nicola Baker
SD
Susan H. Davis
KEYWORDS
medicinal chemistry programhuman african trypanosomiasisdiaminothiazole series confirmeddependent kinase crk12action studies revealedlead compound capabledose intramuscular treatmentcuring cattle infectedpromising compoundurgent needtrypanosoma vivaxsoluble analoguessaharan africarelated analoguesmajor problemeffective drugsdrug resistancecurrent treatmentscomprehensive modecaused principally