A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.

Cell chemical biology, Volume: 27, Issue: 5
May 21, 2020
Daigo Inoyama D, Divya Awasthi D, Glenn C Capodagli GC, Kholiswa Tsotetsi K, Paridhi Sukheja P, Matthew Zimmerman M, Shao-Gang Li SG, Ravindra Jadhav R, Riccardo Russo R, Xin Wang X, Courtney Grady C, Todd Richmann T, Riju Shrestha R, Liping Li L, Yong-Mo Ahn YM, Hsin Pin Ho Liang HP, Marizel Mina M, Steven Park S, David S Perlin DS, Nancy Connell N, Véronique Dartois V, David Alland D, Matthew B Neiditch MB, Pradeep Kumar P, Joel S Freundlich JS

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.

Courtesy of the U.S. National Library of Medicine