Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
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| Enthalten in: |
Journal of medicinal chemistry - 65(2022), 7 vom: 14. Apr., Seite 5606-5624 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Smith, Alasdair [VerfasserIn] |
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| Links: |
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| Themen: |
Cyclin-Dependent Kinases |
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| Anmerkungen: |
Date Completed 15.04.2022 Date Revised 31.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.1c02104 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM338339620 |
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| 245 | 1 | 0 | |a Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis |
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| 520 | |a 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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| 700 | 1 | |a Rowan, Tim |e verfasserin |4 aut | |
| 700 | 1 | |a Rico Vidal, Eva |e verfasserin |4 aut | |
| 700 | 1 | |a Stojanovski, Laste |e verfasserin |4 aut | |
| 700 | 1 | |a Huggett, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Hampton, Shahienaz E |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Corpas Lopez, Victoriano |e verfasserin |4 aut | |
| 700 | 1 | |a Gillingwater, Kirsten |e verfasserin |4 aut | |
| 700 | 1 | |a Duke, Jeff |e verfasserin |4 aut | |
| 700 | 1 | |a Napier, Grant |e verfasserin |4 aut | |
| 700 | 1 | |a Peter, Rose |e verfasserin |4 aut | |
| 700 | 1 | |a Vitouley, Hervé S |e verfasserin |4 aut | |
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| 700 | 1 | |a Milne, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Jeacock, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Nicola |e verfasserin |4 aut | |
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| 700 | 1 | |a Witty, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Wyllie, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Read, Kevin D |e verfasserin |4 aut | |
| 700 | 1 | |a Gilbert, Ian H |e verfasserin |4 aut | |
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