Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma

首创肌球蛋白 10 抑制剂作为胶质母细胞瘤新靶标的药物发现

• 批准号: 10595848
• 负责人: Theodore M Kamenecka
• 金额: $ 22.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595848
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; ATP-G-actin; Actins; Area; Back; Basic Science; Binding Proteins; Biochemical; Biological Assay; Biology; Brain; Cells; Chemicals; Clinical Treatment; DNA Damage; Data; Dependence; Development; Diagnosis; Dose; Drug Kinetics; Excision; FDA approved; Funding Mechanisms; Future; Glioblastoma; Goals; Hand; Human; Impairment; In Vitro; Industrialization; Lead; Left; Libraries; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Metabolic stress; Microsomes; Miniaturization; Molecular; Molecular Motors; Molecular Probes; Myosin ATPase; Myosin Type II; Nonmuscle Myosin Type IIA; Patients; Penetrance; Penetration; Pharmaceutical Chemistry; Pharmacology; Phase; Plasma Proteins; Preclinical Testing; Process; Property; Radiation therapy; Readiness; Recurrence; Reproducibility; Research; Research Personnel; Robotics; Running; Skeletal Muscle Myosins; Solubility; Specificity; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Titrations; Toxic effect; Work; antitumor effect; base; biological adaptation to stress; cheminformatics; chemotherapy; counterscreen; cytotoxicity; drug development; drug discovery; drug metabolism; effective therapy; high throughput screening; in vivo; inhibitor; inorganic phosphate; interest; lead optimization; miniaturize; mouse model; neoplastic cell; novel; pharmacophore; prevent; response; scaffold; screening; small molecule; small molecule inhibitor; standard of care; targeted treatment; therapeutic target; translational potential; tumor

PROJECT SUMMARY An area of significant unmet need is the effective treatment of glioblastoma (GBM), an aggressive, fast-growing brain cancer that represents 48% of all malignant brain tumors. If left untreated, GBM is typically fatal within three months. Due to a high rate of recurrence, the current standard of care, consisting of safe maximal tumor resection, radiation therapy and chemotherapy, only extends survival following initial diagnosis to 1 year, with <5% of patients surviving longer than five years. Invasion and proliferation are defining hallmarks of cancer, and in GBM, blocking one stimulates the other. This implies that effective therapy requires inhibiting both simultaneously. We have found that the molecular motor myosin 10 (Myo10) meets these criteria. Myo10 deletion impairs invasion, slows proliferation, and prolongs survival in murine models of GBM. Although tumors still form, Myo10 deletion also enhances tumor cell dependency on both DNA damage and metabolic stress responses, inducing synthetic lethality when combined with FDA approved inhibitors of these processes. Results demonstrate that a therapeutic strategy targeting Myo10 is expected to be tolerated and have an anti- tumor effect that can also synergize with established therapies. However, pursuing the translational potential of Myo10 in GBM has been limited by the complete lack of molecular probes for this myosin. Thus, the overall goal of this proposal is to perform a large scale high throughput screening (HTS) campaign in the R61 phase using the Scripps Institutional Drug Discovery Library (SDDL) of >665,000 compounds to identify and subsequently validate, characterize and optimize first-in-class therapeutic agents targeting Myo10 in the R33 phase. Successful transition to the R33 phase will be determined by the Go/No-Go criteria of identifying at least two chemically distinct structural scaffolds for optimization. Far more are anticipated and plans are in place to prioritize hits. The inter-disciplinary team of investigators combines uniquely complementary expertise in GBM, myosin biology, HTS screening, medicinal chemistry, drug development and the clinical treatment of GBM. Preliminary data garnered from a 1.28K compound LOPAC screen demonstrates that the project is ready for a full-scale HTS campaign, having demonstrated the primary assay is HTS compatible with an excellent Z’, high assay reproducibility and a lack of false positives. Readiness is further supported by a counterscreen in place that utilizes the same approach as the primary screen, titration assays and a comprehensive screening funnel to support the medicinal chemistry. A primary lead and a back-up resulting from these efforts will then be advanced under a different funding mechanism for development as a GBM treatment (e.g. IGNITE in vivo efficacy PAR-18-761 and BPN Small Molecule Drug Discovery and Development PAR-20-122). Further, we anticipate that the resulting small molecule inhibitors of Myo10 will enable discovery of indications in addition to GBM where its modulation would be therapeutically beneficial.

项目摘要 一个明显未满足的区域是有效治疗胶质母细胞瘤（GBM），这是一种侵略性，快速增长 脑癌占所有恶性脑肿瘤的48％。如果未经治疗，GBM通常是致命的 三个月。由于复发率高，当前的护理标准由安全最大肿瘤组成 切除，放射治疗和化学疗法仅在初始诊断后将生存扩展到1年，而 <5％的患者生存时间超过五年。入侵和扩散是癌症的标志， 在GBM中，阻止一个刺激另一个刺激。这意味着有效的治疗需要抑制 相似地。我们发现分子运动肌球蛋白10（MyO10）符合这些标准。 myo10 删除会损害入侵，减慢增殖并延长GBM鼠模型中的生存​​。虽然肿瘤 仍然形成MyO10删除还可以增强肿瘤细胞对DNA损伤和代谢应激的依赖性 当与FDA认可的这些过程的抑制剂结合使用时，响应，诱导合成杀伤力。 结果表明，针对Myo10的治疗策略有望容忍，并具有抗 肿瘤作用也可以与已建立的疗法协同作用。但是，追求翻译潜力 GBM中的myo10受到这种肌球蛋白缺乏分子问题的限制。那，总体 该建议的目标是在R61阶段进行大规模的高吞吐量筛查（HTS）广告系列 使用> 665,000种化合物的Scripps机构药物发现库（SDDL）来识别和 随后验证，表征和优化针对R33中MYO10的第一类治疗剂 阶段。成功过渡到R33阶段将取决于识别AT的GO/No-Go标准 至少两个化学上不同的结构支架进行优化。预计会有更多的预期 优先点击的位置。研究人员跨学科团队结合了独特的完善专业知识 在GBM中，肌球蛋白生物学，HTS筛查，医学化学，药物开发和临床治疗 GBM。从1.28K复合LOPAC屏幕获得的初步数据表明该项目是 准备进行全面的HTS运动，证明了主要测定法与HTS兼容 出色的Z’，高分测定可重复性和缺乏误报。准备进一步支持 使用与主屏幕相同的方法，滴定测定和A 全面筛查漏斗以支持医学化学。主要领先优势和备份 然后，从这些努力中，将在与GBM的开发资金机制下进行进步 治疗（例如，INDITE在体内效率PAR-18-761和BPN小分子药物发现和 开发20-122）。此外，我们预计由Myo10的小分子抑制剂将 除了GBM之外，还可以发现其调制将是热有益的。