Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma

开发用于治疗胶质母细胞瘤的非肌肉肌球蛋白 II 抑制剂

基本信息

批准号：
10524193
负责人：
Courtney A Miller
金额：
$ 16.11万
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：
2021-01-01 至 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524193
关键词：
Achievement Area Award Basic Science Biological Assay Biological Availability Biology Brain Neoplasms Cell Death Cell Line Cell division Cells Characteristics Chemoresistance Clinic Clinical Clinical Treatment Cytokinesis Development Diagnosis Dose Drug Addiction Excision Family Frequencies Funding Future Glioblastoma Goals Half-Life In Vitro Lead Left Malignant neoplasm of brain Maximum Tolerated Dose Measures Methamphetamine use disorder Modeling Molecular Motors Mus Myosin ATPase Myosin Type II Oral Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Polyploidy Positioning Attribute Property Radiation Radiation therapy Recurrence Research Route Safety TP53 gene Testing Therapeutic Therapeutic Index United States National Institutes of Health Work analog blebbistatin chemotherapy course development disorder later incidence prevention drug development effective therapy efficacy study efficacy testing experimental study gene therapy improved in vivo in vivo Model inhibitor methamphetamine use migration mouse model neoplastic cell non-muscle myosin pre-clinical preclinical study predict responsiveness programs radioresistant response scale up screening small molecule small molecule inhibitor standard of care synergism therapeutic target translational potential tumor

项目摘要

PROJECT SUMMARY An area of significant unmet need is the treatment of glioblastoma (GBM), an aggressive, fast-growing and lethal brain cancer that represents 15% of all brain tumors. If left untreated, GBM is typically fatal within three months. And, 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 one year. Invasion and proliferation are defining phenotypes of GBM, and GBM cells do only one or the other. However, blocking invasion stimulates proliferation and vice versa, implying that an ideal therapeutic target must satisfy 2 criteria: 1) drive both invasion and proliferation and 2) block both when inhibited, even when their pathways are active. Through extensive genetic interventions, nonmuscle myosin II (NMII) family of molecular motors has been shown to meet these criteria. However, the translational potential of this research has been limited by the lack of a clinically safe, CNS-penetrant NMII small molecule inhibitor. Following medicinal chemistry efforts supported by a Blueprint Neurotherapeutics (BPN) award, clinically safe derivatives of the small molecule NMII allosteric inhibitor Blebbistatin are under development as a treatment for drug addiction. Development of this class of compounds has enabled preliminary proof-of-principle studies indicating that these NMII inhibitors significantly improve survival in an aggressive murine model of GBM, likely through the inhibition of cytokinesis (cell division) and eventual GBM cell death. The overarching goal of the current proposal is to advance the potential for treating GBM with an NMII small molecule inhibitor by positioning the program to be competitive for entry into the BPN. The R61 Phase (Year 1) will consist of [1] scale up of the lead compound, SR-561, [2] in vitro screening of GBM cell lines to aid selection of in vivo efficacy murine models to be used in the R33 phase and [3] initiation of medicinal chemistry to further optimize SR-561 to improve properties aimed at the specific therapeutic needs of a GBM treatment. Following successful achievement of the milestones detailed in the proposal, the R33 Phase (Years 2 and 3) will involve [1] a continuation of compound optimization by medicinal chemistry, [2] in vivo efficacy testing with SR-561 and an optimized analog, [3] in vitro and in vivo DMPK profiling and [4] compound tolerability testing. The proposed work is expected to establish the necessary parameters for successful entry into the BPN program to advance an NMII small molecule inhibitor to the clinic for the treatment of GBM.

项目摘要未满足的重要区域是治疗胶质母细胞瘤（GBM），一种侵略性，快速增长且致命的脑癌占所有脑肿瘤的15％。如果未治疗，GBM通常在三个月内致命。并且，由于复发率高，当前的护理标准包括安全的最大肿瘤切除术，放射疗法和化学疗法仅在初始诊断后将生存扩展到一年。入侵和增殖是定义GBM的表型，而GBM细胞仅做一个或另一种。但是，阻止入侵刺激增殖，反之亦然，这意味着理想的治疗靶标必须满足2个标准： 1）驱动入侵和增殖，以及2）抑制时，即使它们的途径处于活动状态，也会阻止两者。通过广泛的遗传干预措施，已经显示了分子电机的非肌肉肌球蛋白II（NMII）家族满足这些标准。但是，这项研究的翻译潜力受到缺乏临床上安全的CNS渗透剂NMII小分子抑制剂。遵循药物化学的努力蓝图神经疗法（BPN）奖，小分子NMII变构的临床安全衍生物抑制剂布列比沙素正在开发中，作为药物成瘾的一种治疗方法。这类的发展化合物已经实现了初步证明，表明这些NMII抑制剂显着在GBM的侵略性鼠模型中提高生存率，可能通过抑制细胞因子（细胞分裂）和最终的GBM细胞死亡。当前提议的总体目标是提高潜力通过将程序定位为有竞争力的进入，用NMII小分子抑制剂治疗GBM BPN。 R61期（1年）将包括[1]缩放铅化合物SR-561，[2]体外筛选 GBM细胞系的用于选择在R33期和[3]启动中使用的体内功效鼠模型药物化学的进一步优化SR-561，以改善针对特定治疗需求的特性 GBM治疗。在提案中详细介绍的里程碑成功实现后，R33阶段（2年和3年）将涉及[1]药物化学的化合物优化的延续，[2]体内使用SR-561和优化的类似物，[3]体外和体内DMPK分析和[4]化合物进行功效测试耐受性测试。预计拟议的工作将建立成功进入的必要参数进入BPN计划，以将NMII小分子抑制剂推向诊所进行GBM的治疗。