A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA. Issue 5 (21st May 2020)

• Record Type: Journal Article
• 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.
• Is Part Of: Cell chemical biology. Volume 27:Issue 5(2020)
• Page Start: 560
• Page End: 570.e10
• Publication Date: 2020-05-21
• Subjects: Mycobacterium tuberculosis -- antitubercular -- structure-based design -- KasA -- pharmacokinetics -- JSF-3285; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.02.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: A structure-based optimization of the KasA inhibitor DG167 led to JSF-3285 The inhibitor evolution focused on metabolic stability and mouse plasma PK JSF-3285 is efficacious in a mouse model of chronic TB infection at 5 mg/kg JSF-3285 represents a preclinical lead compound for TB Abstract : Inoyama et al. disclose the optimization of an indazole antitubercular targeting the β-ketoacyl-ACP synthase KasA. A structure-based approach has overcome significant issues with mouse metabolic stability and pharmacokinetics. A preclinical drug candidate has been delivered with efficacy in a mouse model of chronic M. tuberculosis infection at 5 mg/kg dosing.