A Preclinical Program for Targeting Mycobacterium tuberculosis KasA

针对结核分枝杆菌 KasA 的临床前计划

基本信息

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
项目类别：
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

项目摘要

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.

抽象的我们在此提出一项资助申请，重点关注后期开发根据我们最近发表的研究，我们已经披露了临床前候选药物 JSF-3285。该程序的起源导致了热门化合物 DG167 的产生并鉴定了在此基础上，我们初步研究了必需的 β-酮酰基合酶 KasA。数据详细说明了 JSF-3285 的优化，该优化在急性和慢性疾病中非常有效小鼠结核分枝杆菌感染慢性模型，剂量低至 5 mg/kg，每日一次该提案旨在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 IND 启用此外，我们根据初步数据提出了第二代方案。由结构独特的酰胺系列组成，具有良好的体外功效，小鼠该资助的第二个目标将利用 PK 和 X 射线结构数据来发展该系列。我们广泛的 X 射线结构数据、SAR 和机器学习模型，可在如果不是等于或超过 JSF-3285 的化合物，则为最低新型早期先导化合物。这两个目标的总和，包括 JSF-3285 和第二代候选目标， KasA 抑制剂很有可能在未来 5 年内变得具有临床意义年。