A Preclinical Program for Targeting Mycobacterium tuberculosis KasA

摘要 我们在此提出了一个赠款申请，重点是后期发展， 临床前候选物JSF-3285。根据我们最近发表的研究，我们发现 这个程序的起源，导致击中化合物DG 167和鉴定的 必需的β-酮酰基合酶KasA作为靶标。在此基础上，我们的初步 数据详细说明了达到JSF-3285的优化，JSF-3285在急性 慢性模型M.在小鼠中以低至5 mg/kg每日一次的剂量感染结核病 口。该提案旨在通过进行必要的药物研究来建立这些数据。 联合和复发研究，以达到临床状态并开始IND启用 问题研究此外，我们根据初步数据提出了第二代方案 由具有有希望的体外功效的结构不同的酰胺系列组成， PK和X射线结构数据。赠款的第二个目标将发展这个系列， 我们广泛的X射线结构数据、SAR和机器学习模型， 如果不是等于或超过JSF-3285的化合物，则最低限度的新型早期先导化合物。 这两个目标的总和，包括JSF-3285和第二代候选人， 这将使KasA抑制剂在未来5年内成为临床相关药物的可能性很高。 年

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.