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

• 批准号: 10557160
• 负责人: Courtney A Miller
• 金额: $ 48.03万
• 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: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557160
• 关键词: Achievement; Area; Award; Basic Science; Biological Assay; Biological Availability; Biology; Brain Neoplasms; Cell Death; Cell Line; Cell division; Cells; Characteristics; Chemoresistance; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Treatment; Cytokinesis; Development; Diagnosis; Dose; Drug Addiction; Excision; Family; Frequencies; Funding; Future; Glioblastoma; Goals; Half-Life; In Vitro; Invaded; 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; Proliferating; Property; Radiation; Recurrence; Research; Route; Safety; TP53 gene; Testing; Therapeutic; Therapeutic Index; United States National Institutes of Health; Work; analog; blebbistatin; chemotherapy; course development; 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; relapse prevention; response; scale up; screening; small molecule; small molecule inhibitor; standard of care; synergism; therapeutic target; translational potential; tumor

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.

项目概要 一个严重未满足需求的领域是胶质母细胞瘤 (GBM) 的治疗，这是一种侵袭性、快速生长和致命的疾病 脑癌占所有脑肿瘤的 15%。如果不及时治疗，GBM 通常会在三个月内致命。 而且，由于复发率很高，当前的护理标准包括安全的最大肿瘤切除术， 放射治疗和化学治疗只能将初次诊断后的生存期延长至一年。入侵和 增殖是 GBM 的定义表型，而 GBM 细胞只执行其中之一。然而，阻止 入侵刺激增殖，反之亦然，这意味着理想的治疗靶点必须满足两个标准： 1) 驱动入侵和增殖，2) 在受到抑制时阻断两者，即使它们的途径处于活跃状态。 通过广泛的基因干预，非肌肉肌球蛋白 II (NMII) 分子马达家族已被证明 以满足这些标准。然而，这项研究的转化潜力因缺乏相关研究而受到限制。 临床安全的中枢神经系统渗透性 NMII 小分子抑制剂。以下药物化学工作的支持 蓝图神经治疗 (BPN) 奖，小分子 NMII 变构的临床安全衍生物 抑制剂 Blebbistatin 正在开发中，作为药物成瘾的治疗方法。该类的开发 化合物已启用初步原理验证研究，表明这些 NMII 抑制剂显着 可能通过抑制胞质分裂（细胞分裂）来提高侵袭性 GBM 小鼠模型的存活率 以及最终 GBM 细胞死亡。当前提案的总体目标是提高潜力 通过将该项目定位为具有竞争性，使用 NMII 小分子抑制剂治疗 GBM BPN。 R61 阶段（第一年）将包括 [1] 先导化合物 SR-561 的放大，[2] 体外筛选 GBM 细胞系，以帮助选择用于 R33 阶段和 [3] 启动的体内功效小鼠模型 药物化学进一步优化 SR-561，以改善针对特定治疗需求的特性 GBM 治疗。在成功实现提案中详述的里程碑之后，R33 阶段 （第 2 年和第 3 年）将涉及 [1] 通过药物化学继续进行化合物优化，[2] 体内 使用 SR-561 和优化类似物、[3] 体外和体内 DMPK 分析以及 [4] 化合物进行功效测试 耐受性测试。拟议的工作预计将为成功进入建立必要的参数 进入 BPN 计划，将 NMII 小分子抑制剂推向临床，用于治疗 GBM。