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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：
10466840
负责人：
Joel Stephen Freundlich
金额：
$ 79.52万
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/10466840
关键词：
Acute Amides Anabolism Applications Grants Binding Biophysics Butane Cell Death Cell Wall Cessation of life Chronic Clinical Collaborations Companions Comprehension Crystallization Data Dose Drug Combinations Drug Kinetics Drug Targeting Drug resistance Drug resistance in tuberculosis Enzymes Essential Genes Exhibits 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 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 analog animal efficacy azetidine base 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 model development nanomolar novel novel therapeutics pandemic disease pre-clinical preclinical development programs resistant strain risk minimization 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.

摘要