期刊
CHEMMEDCHEM
卷 6, 期 12, 页码 2214-2224出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201100344
关键词
CRK3; cyclin-dependent cdc2-related kinases; leishmaniasis; triazolopyridines; ureas
资金
- Wellcome Trust [077705, WT083481]
- Medical Research Council [G0400028] Funding Source: researchfish
- MRC [G0400028] Funding Source: UKRI
New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of similar to 3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.
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