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A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-03-19 , DOI: 10.1016/j.chembiol.2020.02.007 Daigo Inoyama 1 , Divya Awasthi 1 , Glenn C Capodagli 2 , Kholiswa Tsotetsi 3 , Paridhi Sukheja 3 , Matthew Zimmerman 4 , Shao-Gang Li 1 , Ravindra Jadhav 1 , Riccardo Russo 3 , Xin Wang 1 , Courtney Grady 3 , Todd Richmann 3 , Riju Shrestha 3 , Liping Li 3 , Yong-Mo Ahn 1 , Hsin Pin Ho Liang 4 , Marizel Mina 4 , Steven Park 4 , David S Perlin 4 , Nancy Connell 3 , Véronique Dartois 4 , David Alland 3 , Matthew B Neiditch 2 , Pradeep Kumar 3 , Joel S Freundlich 5
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-03-19 , DOI: 10.1016/j.chembiol.2020.02.007 Daigo Inoyama 1 , Divya Awasthi 1 , Glenn C Capodagli 2 , Kholiswa Tsotetsi 3 , Paridhi Sukheja 3 , Matthew Zimmerman 4 , Shao-Gang Li 1 , Ravindra Jadhav 1 , Riccardo Russo 3 , Xin Wang 1 , Courtney Grady 3 , Todd Richmann 3 , Riju Shrestha 3 , Liping Li 3 , Yong-Mo Ahn 1 , Hsin Pin Ho Liang 4 , Marizel Mina 4 , Steven Park 4 , David S Perlin 4 , Nancy Connell 3 , Véronique Dartois 4 , David Alland 3 , Matthew B Neiditch 2 , Pradeep Kumar 3 , Joel S Freundlich 5
Affiliation
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Published Mycobacterium tuberculosis β-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.
中文翻译：
针对结核分枝杆菌KasA的临床前候选药物。
已公开的结核分枝杆菌β-酮酰基-ACP合酶KasA抑制剂缺乏足够的效力和/或药代动力学特性。基于结构的方法用于优化现有的KasA抑制剂DG167。这使吲唑JSF-3285的小鼠血浆暴露增加了30倍。生化，遗传和X射线研究证实JSF-3285靶向KasA。JSF-3285在急性小鼠感染模型和相应的慢性感染模型中具有显着活性，每天一次口服剂量低至5 mg / kg时有效减少了菌落形成单位，并提高了一线疗效药物异烟肼或利福平。JSF-3285是结核病的有希望的临床前候选药物。
更新日期：2020-03-19
中文翻译：
针对结核分枝杆菌KasA的临床前候选药物。
已公开的结核分枝杆菌β-酮酰基-ACP合酶KasA抑制剂缺乏足够的效力和/或药代动力学特性。基于结构的方法用于优化现有的KasA抑制剂DG167。这使吲唑JSF-3285的小鼠血浆暴露增加了30倍。生化，遗传和X射线研究证实JSF-3285靶向KasA。JSF-3285在急性小鼠感染模型和相应的慢性感染模型中具有显着活性，每天一次口服剂量低至5 mg / kg时有效减少了菌落形成单位，并提高了一线疗效药物异烟肼或利福平。JSF-3285是结核病的有希望的临床前候选药物。
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