A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Abstract

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. 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.