New targets against tuberculosis

防治结核病的新目标

• 批准号: 10197774
• 负责人: DEBORAH T HUNG
• 金额: $ 107.68万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197774
• 关键词: Address; Ames Assay; Anabolism; Animal Model; Animals; Antibiotics; Automobile Driving; Basic Science; Binding; Bioavailable; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biological Assay; Biological Availability; Biology; Cause of Death; Cells; Chemicals; Chronic; Clinical; Communicable Diseases; Crystallization; Data; Development; Discipline; Disease; Drug Interactions; Drug resistance; Drug resistance in tuberculosis; Ensure; Enzymes; Fatty Acids; Genetic study; Goals; HIV; Health; Homologous Gene; Human; In Vitro; Industry; Industry Standard; Infection; Investigational Drugs; Ligase; Light; Maximum Tolerated Dose; Measures; Modeling; Molecular Mechanisms of Action; Mus; Mutagenicity Tests; Mycobacterium tuberculosis; Mycolic Acid; Oral; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Property; Research; Resistance; Role; Safety; Scientist; Series; Solubility; Structure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicogenomics; Translating; Translations; Treatment Efficacy; Tuberculosis; Work; acute infection; analog; animal efficacy; axenic culture; bactericide; base; biophysical analysis; biophysical properties; chronic infection; clinical candidate; clinical practice; combat; design; drug development; efficacy study; first-in-human; human study; in vivo; in vivo evaluation; in vivo monitoring; inhibitor/antagonist; interdisciplinary collaboration; isoniazid; lead candidate; lead optimization; macrophage; mouse model; multiple drug use; novel; novel therapeutics; pandemic disease; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical safety; quinoline; receptor; safety assessment; safety study; structural biology; synergism; therapeutic candidate; therapeutic development; therapeutic target; tuberculosis drugs; tuberculosis treatment

ABSTRACT Tuberculosis is the leading causes of death by infectious diseases worldwide, having recently surpassed HIV and killing an estimated 1.4 million people annually. Drug resistant tuberculosis is becoming an increasing problem, including the recent emergence of strains that have been designated “totally drug resistant,” with relatively few options in the drug development pipeline to combat this crisis. The problem of drug resistance is now posing a serious threat to the management of TB and human health. Increased efforts are urgently needed to identify new therapeutic candidates that are active against drug resistant Mycobacterium tuberculosis. To address this need, we propose to advance a novel chemical class of compounds, 4,6-diaryl substituted quinolines that we have designed to target M. tuberculosis by a new mechanism of action. Importantly, we have demonstrated that this class has excellent in vivo animal efficacy against TB when administered once-a-day and orally, a barrier passed by very few molecules at the discovery stage. In fact, the lead candidate has an ED50 in infected mice of 4.9 mg/kg, which makes it on par with some of the most potent current anti-tubercular drugs. These substituted quinolines are bactericidal against M. tuberculosis by inhibiting the enzymatic function of a new target, FadD32, for which there is no human homologue. Importantly, Fad32 is an essential enzyme in mycolic acid biosynthesis, a well-validated pathway for therapeutic targeting as illustrated by the prominent role played by another inhibitor of this pathway, isoniazid, in current TB therapy. New molecules that hit novel targets in validated pathways have the dual advantage of a high likelihood of therapeutic efficacy based on a proven mechanism of action while overcoming the high levels of resistance to current inhibitors of the pathway. Given that it has been extremely challenging to translate animal to human efficacy, inhibiting pathways or functions that have successfully been targeted by current TB therapy increases the likelihood of successful translation. One of the major hurdles to the successful translation of basic discovery research has been the gap between the initial basic research discovery and therapeutic development. We propose to develop the 4,6-diaryl quionlines in a seamless, interdisciplinary collaboration between leading academic scientists and industry professionals, all who have worked together previously, who will span the disciplines of TB biology, biochemistry, structural biology, medicinal chemistry, and pre-clinical PK/ADME/toxicity in order to progress this promising candidate through the preclinical development of TB therapeutics, from lead optimization to IND filing.

摘要 结核病是全世界传染病导致死亡的主要原因，最近已超过 艾滋病毒每年造成约140万人死亡。耐药结核病正在成为一种日益严重的 问题，包括最近出现的菌株已被指定为“完全耐药”， 药物开发管道中应对这一危机的选择相对较少。抗药性的问题是 现在对结核病的管理和人类健康构成严重威胁。迫切需要加强努力 以鉴定对耐药结核分枝杆菌有活性的新的治疗候选物。 为了满足这一需求，我们提出了一种新的化合物，4，6-二芳基取代的 我们设计的靶向M的喹啉。结核病的一种新的作用机制。重要的是我们有 证明了当每天给药一次时，这类药物对TB具有优异的体内动物功效， 口服，在发现阶段很少有分子通过的屏障。事实上，主要候选人的ED 50 感染小鼠的剂量为4.9 mg/kg，这使其与目前一些最有效的抗结核药物相当。 这些取代的喹啉对M.结核病通过抑制酶的功能， 新的目标，FadD 32，没有人类同源物。重要的是，Fad 32是一种重要的酶， 分枝菌酸生物合成，一种经过充分验证的治疗靶向途径， 在目前的结核病治疗中，这一途径的另一种抑制剂异烟肼发挥了重要作用。击中新目标的新分子 具有双重优势，即基于已证实的 这一作用机制，同时克服了对途径的当前抑制剂的高水平抗性。给定 将动物的功效转化为人类的功效，抑制 已被当前结核病治疗成功靶向的基因增加了成功翻译的可能性。 基础发现研究成功转化的主要障碍之一是差距 在最初的基础研究发现和治疗发展之间。我们建议开发4，6-二芳基 quionlines在领先的学术科学家和行业之间的无缝，跨学科的合作 专业人员，所有谁曾在一起工作过，谁将跨越结核病生物学，生物化学， 结构生物学、药物化学和临床前PK/ADME/毒性，以推进这一有前途的研究。 从先导药物优化到IND申请，通过结核病治疗药物的临床前开发为候选药物提供支持。

项目成果

Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors.

• DOI: 10.1016/j.bmcl.2018.09.037
• 发表时间: 2018-12-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Fang C;Lee KK;Nietupski R;Bates RH;Fernandez-Menendez R;Lopez-Roman EM;Guijarro-Lopez L;Yin Y;Peng Z;Gomez JE;Fisher S;Barros-Aguirre D;Hubbard BK;Serrano-Wu MH;Hung DT
• 通讯作者: Hung DT