Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis

QcrB 杂环抑制剂作为结核病新药

• 批准号: 10385057
• 负责人: THOMAS Joseph HANNAN
• 金额: $ 100万
• 依托单位: FIMBRION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385057
• 关键词: Acute; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Antitubercular Antibiotics; Bacteria; Biological; Biological Availability; Canis familiaris; Cells; Chronic; Clinical; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Complex; Cytochrome bc1 Complex; Cytochromes; Development; Disease; Drops; Drug Interactions; Drug Kinetics; Drug Synergism; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Electron Transport; Energy Metabolism; Exhibits; Explosion; Family; Funding; Goals; Half-Life; HepG2; Hour; Hypoxia; In Vitro; Industry; Infection; Infectious Agent; Intellectual Property; Intravenous; Lead; Liver Microsomes; Lung infections; Mammals; Metabolic; Mission; Modeling; Mus; Mycobacterium tuberculosis; Newly Diagnosed; Oral; Outcome; Oxidases; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Plasma; Prevalence; Property; Proteins; Rattus; Regimen; Resistance; Resistance profile; Respiration; Respiratory Chain; Risk; Safety; Selection Criteria; Series; Small Business Innovation Research Grant; Solubility; Stains; Testing; Therapeutic; Time; Toxic effect; Tuberculosis; United States National Institutes of Health; Work; bactericide; base; clinical candidate; clinical development; clinically relevant; combat; commercial application; drug candidate; drug discovery; drug-sensitive; druggable target; human mortality; improved; in vitro activity; in vivo; indexing; inhibitor; inhibitor therapy; interest; lead series; macrophage; medication safety; mortality; mouse model; mycobacterial; nanomolar; non-tuberculosis mycobacteria; novel; novel drug class; novel therapeutics; phase 2 study; resistance mechanism; respiratory; small molecule; standard of care; success; synergism; therapeutic target; therapeutically effective; tuberculosis drugs; tuberculosis treatment

Project Summary/Abstract 1 Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading 2 cause of mortality due to infection, globally. In 2019, 10 million people were newly diagnosed with TB and 1.5 3 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by 4 drug-resistant Mtb 5 is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitve 6 TB (DS-TB), which results in poor compliance. Treatment for DR-TB is even longer, ranging from 6-24 months 7 typically, with 3, 4 or more antibiotics taken in combination. Despite the dire need for new treatments against 8 DR-TB, only one new antibiotic for TB with an entirely novel mechanism of action (MoA) has been approved in 9 the past 40 years, bedaquiline. Therefore, new classes of drugs with new MoAs that can be combined with 10 existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts 11 energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied 12 an explosion of drug discovery targeting respiration in Mtb. Fimbrion is developing a thienopyrimidine small 13 molecule series that targets the Mtb QcrB protein 14 electron transport chain in Mtb, has been validated as a drug target by the early clinical success of the QcrB 15 inhibitor, Q203, which is currently in Phase 2 clinical trials, but has potential liabilities. Our goal in this project is 16 to develop a best-in-class QcrB inhibitor that could become part of a shorter drug regimen that effectively treats 17 both DS- and DR-TB. Initially in our Phase I project, we had examples of some very potent compounds, but 18 metabolic stability was poor. Our Phase I goals, therefore, were to optimize stability, while maintaining or 19 improving potency, so that we could test lead compounds in an animal model of Mtb infection. We achieved 20 this goal, identifying a lead THP series of stable QcrB inhibitors with low nM potency, favorable PK properties, 21 including oral bioavailability, and demonstrated in vivo efficacy in a mouse model of acute TB infection. In our 22 Phase II project, we will optimize our lead series with the goal of identifying and de-risking a clinical candidate 23 molecule that is effective in treating TB. Specifically, we will 1) further optimize our lead series to improve drug- 24 like properties and pharmacokinetics, while maintaining or improving our current in vitro potency and in vivo 25 efficacy; 2) investigate: i) the efficacy of lead compounds against diverse Mtb stains and under clinically 26 relevant conditions, ii) the risk of resistance, iii) potential in vitro synergy with other anti-Mtb drugs, and iv) in 27 vitro toxicity and potential adverse drug-drug interactions; and 3) test advanced lead compounds for efficacy in 28 clinically relevant mouse models of TB disease and assess in vivo PK and toxicity in larger mammals to select 29 and de-risk a clinical candidate. Successful completion of this project will lead to the identification of a clinical 30 candidate drug that will proceed to pre-IND studies and attract interest from potential co-development partners. strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics for the treatment of TB. QcrB, a component of the respiratory

项目摘要/摘要 由结核分枝杆菌(Mtb)感染引起的结核病(TB)是主要的 2全球感染致死原因。2019年新增结核病患者1000万人和150万人 有300万人死于这种疾病。随着治疗结核病的努力扩大，由结核病引起的感染的流行 4株耐药结核分枝杆菌 5正在增加，部分原因是药物敏感的联合治疗(4种抗生素)持续时间较长(6个月) 6 TB(DS-TB)，导致合规性较差。DR-TB的治疗时间更长，从6个月到24个月不等 通常情况下，联合服用3、4或更多的抗生素。尽管迫切需要新的治疗方法 8耐药结核病，只有一种全新作用机制(MOA)的结核病新抗生素在#年获得批准 在过去的40年里，贝达奎琳。因此，具有新MOAS的新类别药物可以与 目前迫切需要10种现有的或正在研制的新的结核病药物。贝达奎兰的成功，它颠覆了 11结核分枝杆菌的能量代谢，并在减少DR-TB的治疗时间方面显示出希望，伴随着 12针对Mtb呼吸的药物发现爆炸式增长。Fimbrion正在开发一种硫代嘧啶小分子 靶向Mtb QcrB蛋白的13个分子系列 Mtb中的14个电子传递链，已被Qcrb的早期临床成功证实为药物靶点 15抑制剂Q203，目前正处于第二阶段临床试验，但有潜在的风险。我们在这个项目中的目标是 16开发一种同类最好的QcrB抑制剂，这种抑制剂可能成为一种更短的有效治疗 17 DS-TB和DR-TB都是。最初在我们的第一阶段项目中，我们有一些非常有效的化合物的例子，但是 18代谢稳定性差。因此，我们的第一阶段目标是优化稳定性，同时保持或 19提高效力，这样我们就可以在结核分枝杆菌感染的动物模型中测试先导化合物。我们实现了 20这一目标，确定具有低NM效力、良好的PK特性、 21包括口服生物利用度，并在急性结核病感染的小鼠模型中证明了体内疗效。在我们的 22第二阶段项目，我们将优化我们的Lead系列，目标是确定并降低临床候选患者的风险 23有效治疗结核病的分子。具体地说，我们将1)进一步优化我们的Lead系列，以改进药物- 24相似的性质和药代动力学，同时保持或改善我们目前的体外效力和体内 25疗效；2)研究：i)先导化合物对各种结核分枝杆菌菌斑的疗效及临床 26相关条件，ii)耐药风险，iii)与其他抗结核分枝杆菌药物的体外协同作用，以及iv) 27体外毒性和潜在的不良药物-药物相互作用；以及3)测试先进的先导化合物在 28只临床相关的小鼠结核病模型，并评估体内PK和毒性，以选择较大的哺乳动物 29，并降低临床候选人的风险。该项目的成功完成将导致确定一个临床 30种候选药物，将继续进行IND前研究，并吸引潜在共同开发伙伴的兴趣。 对一种或多种一线标准(SOC)抗生素耐药的菌株(DR-TB) 用于治疗结核病。Qcrb，呼吸道的一种成分