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 一个显著未满足需求的领域是胶质母细胞瘤（GBM）的有效治疗，GBM是一种侵袭性、快速生长的肿瘤， 占所有恶性脑肿瘤的48%。如果不治疗，GBM通常是致命的， 三个月由于复发率高，目前的标准治疗，包括安全的最大肿瘤 手术切除、放疗和化疗，仅能将初次诊断后的生存期延长至1年， <5%的患者存活时间超过5年。侵袭和增殖是癌症的标志， 而在GBM中，阻断其中一个会刺激另一个这意味着有效的治疗需要同时抑制 同步我们已经发现分子运动肌球蛋白10（Myo 10）符合这些标准。Myo10 在GBM的鼠模型中，缺失损害侵袭、减缓增殖和存活。虽然肿瘤 Myo 10缺失仍然可以增强肿瘤细胞对DNA损伤和代谢应激依赖性 反应，当与FDA批准的这些过程的抑制剂组合时诱导合成致死性。 结果表明，靶向Myo 10的治疗策略预期是耐受的，并且具有抗肿瘤活性。 也可以与已建立的疗法协同作用。然而，追求翻译的潜力， GBM中的Myo 10由于完全缺乏这种肌球蛋白的分子探针而受到限制。由此可见，总体 该计划的目标是在R61阶段进行大规模的高通量筛选（HTS）活动 使用Scripps Institutional Drug Discovery Library（SDDL）的超过665，000种化合物来识别和 随后在R33中验证、表征和优化针对Myo 10的一流治疗药物 相位成功过渡到R33阶段将取决于确定以下方面的Go/No-Go标准： 用于优化的至少两种化学上不同的结构支架。预计会有更多的计划， 一个可以优先处理袭击的地方跨学科的调查员团队结合了独特的互补专业知识， 在GBM，肌球蛋白生物学，HTS筛选，药物化学，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活动，已证明主要检测试剂盒与HTS兼容， 优异的Z '，高测定再现性和缺乏假阳性。准备工作还得到以下方面的支持： 使用与初级筛选相同的方法进行适当的反筛选，滴定测定和 全面的筛选漏斗，以支持药物化学。一条主要线索和一条后备线索 然后，将在不同的资金机制下推进这些努力， 治疗（例如IGNITE体内疗效PAR-18-761和BPN小分子药物发现和 开发PAR-20-122）。此外，我们预期所得的Myo 10小分子抑制剂将 能够发现除GBM之外的适应症，其中其调节将在治疗上有益。