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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：
10355649
负责人：
Theodore M Kamenecka
金额：
$ 18.54万
依托单位：
SCRIPPS 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 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355649
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.

项目总结