A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.
Clicks: 254
ID: 100929
2020
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.
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inoyama2020acell
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| Authors | Inoyama, Daigo;Awasthi, Divya;Capodagli, Glenn C;Tsotetsi, Kholiswa;Sukheja, Paridhi;Zimmerman, Matthew;Li, Shao-Gang;Jadhav, Ravindra;Russo, Riccardo;Wang, Xin;Grady, Courtney;Richmann, Todd;Shrestha, Riju;Li, Liping;Ahn, Yong-Mo;Ho Liang, Hsin Pin;Mina, Marizel;Park, Steven;Perlin, David S;Connell, Nancy;Dartois, Véronique;Alland, David;Neiditch, Matthew B;Kumar, Pradeep;Freundlich, Joel S; |
| Journal | cell chemical biology |
| Year | 2020 |
| DOI | S2451-9456(20)30071-4 |
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