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.

项目总结 一个重要的未得到满足的领域是对胶质母细胞瘤(GBM)的有效治疗，这是一种侵袭性的、快速增长的 脑癌占所有恶性脑瘤的48%。如果不治疗，GBM通常会在 三个月。由于复发率高，目前的护理标准是安全的最大限度的肿瘤 切除、放射治疗和化疗只能将初次诊断后的生存期延长到1年， 5%的患者存活时间超过五年。侵袭和增殖是癌症的特征， 而在GBM中，阻断一个刺激另一个。这意味着有效的治疗需要抑制两者。 同时。我们发现，分子马达肌球蛋白10(Myo10)满足这些标准。Myo10 在小鼠GBM模型中，缺失会削弱侵袭力，减缓增殖，延长生存期。虽然肿瘤 同样，Myo10缺失也增强了肿瘤细胞对DNA损伤和代谢应激的依赖性 当与FDA批准的这些过程的抑制剂联合使用时，会导致合成致死。 结果表明，以Myo10为靶点的治疗策略有望被耐受，并具有抗 肿瘤效应也可以与已有的治疗方法协同作用。然而，追求的翻译潜力 由于完全缺乏这种肌球蛋白的分子探针，Myo10在GBM中的表达受到了限制。因此，总体上， 该提案的目标是在R61阶段执行大规模高通量筛选(HTS)活动 使用斯克里普斯机构药物发现库(SDDL)中的665,000种化合物来鉴定和 随后验证、鉴定和优化针对R33中Myo10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项目的通过/不通过标准 至少两个化学上截然不同的结构支架进行优化。预计会有更多，计划也在进行中 确定命中优先顺序的位置。跨学科的调查团队结合了独特的互补专业知识 在GBM、肌球蛋白生物学、HTS筛查、药物化学、药物开发和临床治疗方面 GBM。从1.28K复合Lopac屏幕获得的初步数据表明，该项目是 已经为全面的HTS活动做好了准备，已经证明了主要的HTS测试与HTS兼容 优良的Z‘，高的检测重复性和无假阳性。就绪性得到进一步支持， 使用与主筛分相同的方法的副筛分、滴定分析和 全面筛选漏斗，支持药物化学。一条主要线索和一条备份结果 从这些努力中，将在不同的发展筹资机制下推进，成为一个基于性别的管理 治疗(例如，点燃体内疗效PAR-18-761和BPN小分子药物发现和 发展PAR-20-122)。此外，我们预计由此产生的Myo10小分子抑制剂将 能够发现除GBM之外的适应症，在那里其调节将是有益的治疗。