IND-enabling studies of the potent LpxC inhibitor LPC-233 as a novel antibiotic against Gram-negative pathogens

有效的 LpxC 抑制剂 LPC-233 作为抗革兰氏阴性病原体的新型抗生素的 IND 启用研究

• 批准号: 10011609
• 负责人: Clayton Duncan
• 金额: $ 79.74万
• 依托单位: VALANBIO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011609
• 关键词: Address; Adverse effects; Anabolism; Anti-Bacterial Agents; Antibiotics; Bacterial Counts; Basic Science; Binding; Biochemical; Biological; Biological Availability; Canis familiaris; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Chemicals; Chromatography; Clinic; Clinical; Clinical Trials; Collaborations; Complex; Continuous Infusion; Cyclic GMP; Data; Development; Diastolic blood pressure; Dose; Dose-Limiting; Drops; Drug resistance; Effectiveness; Enterobacteriaceae; Enzyme Inhibitor Drugs; Enzymes; Escherichia coli; Family; Focal Infection; Formulation; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Head; Healthcare; Hospitals; Hour; Human; Hydrophobicity; In Vitro; Incidence; Infection; Infusion procedures; Intention; Investigation; Kilogram; Kinetics; Klebsiella pneumoniae; Lactamase; Lead; Legal patent; Lipid A; Lipids; Lipopolysaccharides; Medical; Membrane; Modeling; Multi-Drug Resistance; Mus; N-acetylglucosamine deacetylase; Oral; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plague; Procedures; Process; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Publications; Rattus; Regimen; Research; Research Activity; Resistance; Route; Safety; Secure; Sepsis; Series; Structure; Superbug; Systemic infection; Testing; Therapeutic; Thigh structure; Toxic effect; Toxicology; Translating; Treatment Protocols; Universities; Work; Yersinia pestis; antimicrobial drug; bactericide; carbapenem resistance; carbapenemase; clinical candidate; cytotoxicity; design; efficacy evaluation; exhaust; fitness; global health; in vivo; inhibitor/antagonist; intravenous administration; lipid biosynthesis; monolayer; mutant; novel; novel therapeutics; pathogen; pathogenic bacteria; posters; professor; research and development; resistance mechanism; safety study; small molecule inhibitor; virtual

Project Summary/Abstract The rapidly increasing incidences of infections caused by multidrug-resistant Gram-negative bacteria represent an emerging global health care crisis. The fact that no new class of medication against Gram- negative bacteria has been introduced into practice over half of a century, combined with the lengthy development and approval process, add to the urgency to accelerate and streamline research and development processes for new treatment approaches to Gram-negative bacterial infections. LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is an essential enzyme in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide and the major lipid component of the outer monolayer of the Gram-negative bacterial outer membrane. Constitutive lipid A biosynthesis is required for bacterial viability and fitness in the human host. As such, LpxC is an attractive target to create a novel class of small molecule inhibitors as antibacterial agents specific to Gram-negative bacterial pathogens. Extensive research over the last two decades shows that (1) potent LpxC inhibitors display outstanding bactericidal effect; (2) with few exceptions in vitro, virtually all Gram-negative bacteria are sensitive to LpxC inhibition in vivo; and (3) LpxC inhibitors are not inactivated by common resistance mechanisms such as extended- spectrum -lactamases (ESBL) or carbapenemases. Although dose-limiting adverse effects have limited the development of the most advanced LpxC inhibitors, ACHN-975 (Achaogen) and RC-0 1 (Recida Therapeutics), these compounds do not show the same liabilities, suggesting that the observed adverse effects do not represent a class limitation. Valanbio Therapeutics was founded to translate basic research activities from Duke University into a potential new class of antibacterial agents against Gram-negative pathogens. Duke University and Valanbio Therapeutics have identified a lead LpxC inhibitor, LPC-233, which we seek to advance to the clinical stage testing. LPC-233 is potently and broadly bactericidal against Gram-negative bacteria in vitro and significantly reduces bacterial counts in the murine thigh infection model at doses as low as 2 mg/kg BID. It also displays an outstanding safety profile in rats. In this proposal, Valanbio Therapeutics plans to (1) develop GMP- compatible large-scale synthesis of LPC-233; (2) continue to evaluate and optimize the efficacy and dosing regimen of LPC-233 against susceptible and multidrug-resistant Gram-negative bacterial pathogens in mice; (3) investigate the potential dose-limiting safety liabilities in vitro and in vivo. The successful execution of the proposed studies will clear the path for IND filing and advance LPC-233 to Phase I human clinical trials.

项目总结/摘要 多重耐药革兰氏阴性菌引起的感染发病率迅速增加 代表着一场新的全球医疗危机。事实上，没有新的药物类别对革兰氏- 阴性细菌已经被引入实践超过半个世纪，再加上漫长的 开发和批准过程，增加了加速和简化研究的紧迫性， 革兰氏阴性细菌感染的新治疗方法的开发过程。 LpxC（UDP-3-O-（R-3-hydroxymyristoyl）-N-乙酰葡糖胺脱乙酰基酶）是一种必需的酶， 脂质A是脂多糖的疏水性锚，也是脂多糖的主要脂质成分， 革兰氏阴性细菌外膜的外单层。组成型脂质A生物合成是必需的 细菌在人类宿主中的生存能力和适应性。因此，LpxC是创建新类的有吸引力的目标 小分子抑制剂作为革兰氏阴性细菌病原体特异性的抗菌剂。广泛 过去二十年的研究表明，（1）有效的LpxC抑制剂显示出出色的杀菌作用， （2）除少数例外外，在体外，几乎所有革兰氏阴性菌对LpxC抑制敏感， 体内;和（3）LpxC抑制剂不被常见的耐药机制灭活，如延长- 广谱β-内酰胺酶（ESBL）或碳青霉烯酶。虽然剂量限制性的不良反应限制了 开发最先进的LpxC抑制剂ACHN-975（Achaogen）和RC-01（Recida Therapeutics）， 这些化合物没有表现出相同的责任，这表明观察到的不利影响并不 这是一个阶级限制。 Valanbio Therapeutics的成立旨在将杜克大学的基础研究活动转化为 针对革兰氏阴性病原体的潜在的新型抗菌剂。杜克大学和瓦兰比奥 治疗已经确定了一种主要的LpxC抑制剂LPC-233，我们试图将其推进到临床阶段。 试验. LPC-233在体外对革兰氏阴性菌具有强效和广泛的杀菌作用， 以低至2 mg/kg BID的剂量降低鼠大腿感染模型中的细菌计数。它还显示 在大鼠中具有出色的安全性。在该提案中，Valanbio Therapeutics计划（1）开发GMP- LPC-233的相容性大规模合成;（2）继续评估和优化疗效和剂量 LPC-233对小鼠中的易感和多重耐药革兰氏阴性细菌病原体的方案; (3)研究体外和体内潜在的剂量限制性安全性责任。的成功执行 拟议的研究将为IND申请扫清道路，并将LPC-233推进到I期人体临床试验。