A Preclinical Program for Targeting Mycobacterium tuberculosis KasA

针对结核分枝杆菌 KasA 的临床前计划

• 批准号: 10681371
• 负责人: Joel Stephen Freundlich
• 金额: $ 79.98万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681371
• 关键词: Acute; Amides; Anabolism; Applications Grants; Binding; Biological; Biophysics; Butane; Cell Death; Cell Wall; Cessation of life; Chronic; Clinical; Collaborations; Companions; Comprehension; Data; Development; Dose; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Enzymes; Essential Genes; Exhibits; Friends; Generations; Goals; Grant; Health Benefit; In Vitro; Indoles; Infection; Lead; Length; Measurable; Microbiology; Modeling; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Mycolic Acid; Oral; Pathogenesis; Pathway interactions; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Predisposition; Probability; Process; Public Health; Publishing; Regimen; Reporting; Research; Research Personnel; Resistance; Resolution; Rifampin; Roentgen Rays; Route; Series; Structure; Sulfonamides; Sum; Time; Treatment Failure; Treatment Protocols; Tuberculosis; United States; Validation; X-Ray Crystallography; analog; animal efficacy; azetidine; clinical candidate; clinically relevant; combinatorial; drug development; drug discovery; drug relapse; experience; experimental study; extensive drug resistance; fatty acid biosynthesis; global health; improved; in vitro activity; in vivo; inhibitor; isoniazid; machine learning model; nanomolar; novel; novel therapeutics; pandemic disease; pre-clinical; preclinical development; programs; resistant strain; risk minimization; risk selection; skills; structural biology; targeted treatment; therapy duration; tuberculosis drugs; tuberculosis treatment

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.

摘要 我们在此提出了一项赠款申请，重点是后期开发 临床前候选JSF-3285。根据我们最近发表的研究，我们披露了 该项目的起源，导致命中化合物DG167和鉴定 以必需的β-酮酰基合成酶KASA为靶标。在这一努力的基础上，我们初步的 数据详细说明了对JSF-3285进行的优化，该优化在急性和慢性疾病中是有效的 每天一次低至5 mg/kg剂量的小鼠慢性结核分枝杆菌感染模型 口头的。这项建议寻求通过进行必要的药物治疗来建立在这些数据的基础上 联合和复发研究以达到临床状态并开始使IND成为可能 学习。此外，我们还提出了基于初步数据的第二代方案 由结构不同的酰胺系列组成，在体外具有良好的疗效 PK和X射线结构数据。赠款的第二个目标将发展本系列，利用 我们丰富的X射线结构数据、合成孔径雷达和机器学习模型 至少新的早期先导化合物，如果不是等于或超过JSF-3285的化合物。 JSF-3285和第二代候选人/S两个目标的总和， 将为KASA抑制剂在未来5年成为临床相关药物提供极大的可能性 好几年了。