A Preclinical Program for Targeting Mycobacterium tuberculosis KasA

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ABSTRACT We present herein a grant application focused on the late-stage development of preclinical candidate JSF-3285. Per our recently published research, we have disclosed the genesis of this program that led to the hit compound DG167 and identification of the essential β-keto acyl synthase KasA as its target. Building on this effort, our preliminary data detail the optimization to arrive at JSF-3285 which is efficacious in the acute and chronic models of M. tuberculosis infection in mice at doses as low as 5 mg/kg once-daily oral. This proposal seeks to build on this data by conducting the requisite drug combination and relapse studies to achieve clinical status and begin IND-enabling studies. In addition, we propose a second generation program based on preliminary data consisting of a structurally distinct amide series with promising in vitro efficacy, mouse PK, and X-ray structural data. The grant's second aim will evolve this series, leveraging our extensive X-ray structural data, SAR, and machine learning models, to produce at minimum novel early lead compounds if not compounds equal to or surpassing JSF-3285. The sum total of the two aims, featuring JSF-3285 and second generation candidate/s, will lend a high probability to a KasA inhibitor becoming clinically relevant in the next 5 years.