期刊
CELL CHEMICAL BIOLOGY
卷 27, 期 5, 页码 560-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2020.02.007
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资金
- NIH [U19AI109713, U19AI142731, R21AI111647, R33AI11167]
Published Mycobacterium tuberculosis beta-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.
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