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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胶质母细胞瘤 (GBM) 是一种侵袭性、快速生长的疾病，其有效治疗尚未得到满足。脑癌占所有恶性脑肿瘤的 48%。如果不及时治疗，GBM 通常会在三个月。由于复发率高，目前的护理标准包括安全最大肿瘤切除、放疗和化疗只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五年。侵袭和增殖是癌症的标志，在 GBM 中，阻断其中一种会刺激另一种。这意味着有效的治疗需要同时抑制同时地。我们发现分子运动肌球蛋白 10 (Myo10) 符合这些标准。妙10 缺失会损害 GBM 小鼠模型的侵袭、减缓增殖并延长生存期。虽然肿瘤虽然 Myo10 缺失仍然存在，但也增强了肿瘤细胞对 DNA 损伤和代谢应激的依赖反应，与 FDA 批准的这些过程的抑制剂结合使用时会诱导合成致死性。结果表明，针对 Myo10 的治疗策略预计具有耐受性并具有抗- 肿瘤效应也可以与现有疗法产生协同作用。然而，追求转化潜力 GBM 中的 Myo10 由于完全缺乏这种肌球蛋白的分子探针而受到限制。因此，总体该提案的目标是在 R61 阶段进行大规模高通量筛选 (HTS) 活动使用包含超过 665,000 种化合物的斯克里普斯机构药物发现库 (SDDL) 来识别和随后在 R33 中验证、表征和优化针对 Myo10 的一流治疗药物阶段。成功过渡到 R33 阶段将取决于确定的 Go/No-Go 标准至少两个化学上不同的结构支架用于优化。更多的预期和计划正在制定中优先点击的地方。跨学科研究团队结合了独特的互补专业知识 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 屏幕收集的初步数据表明该项目是已证明主要检测方法与 HTS 兼容，已为全面的 HTS 活动做好准备出色的 Z'、高测定重现性且无假阳性。准备工作得到进一步支持反筛选到位，采用与主筛选相同的方法、滴定测定和支持药物化学的综合筛选漏斗。主要线索和备用线索这些努力将在不同的融资机制下推进，作为 GBM 治疗（例如 IGNITE 体内功效 PAR-18-761 和 BPN 小分子药物发现和开发 PAR-20-122）。此外，我们预计由此产生的 Myo10 小分子抑制剂将使得能够发现除 GBM 之外的适应症，其调节将在治疗上有益。