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: 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
• 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

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.

项目总结 一个重要的未得到满足的领域是胶质母细胞瘤(GBM)的治疗，这是一种侵袭性、快速生长和致命的肿瘤 脑癌占所有脑瘤的15%。如果不治疗，GBM通常会在三个月内致命。 而且，由于复发率很高，目前的护理标准是安全地最大限度地切除肿瘤， 放射治疗和化疗只能将初次诊断后的存活期延长到一年。入侵和 增殖是决定基底膜的表型，而基底膜细胞只具有其中的一种。但是，阻止 侵袭刺激增殖，反之亦然，这意味着理想的治疗目标必须满足两个标准： 1)同时促进侵袭和增殖，2)抑制时两者都被阻断，即使它们的通路是活跃的。 通过广泛的遗传干预，非肌肉肌球蛋白II(NMII)家族的分子马达已被证明 来满足这些标准。然而，这项研究的翻译潜力受到了缺乏 临床安全，中枢神经系统穿透性NMII小分子抑制剂。在药物化学方面的努力得到了 小分子NMII变构的临床安全衍生物蓝图神经治疗学(BPN)奖 抑制剂blbbistatin正在开发中，作为一种药物成瘾的治疗方法。这一类人的发展 化合物使得初步的原理验证研究表明，这些NMII抑制剂显著地 提高侵袭性GBM小鼠模型的存活率，可能是通过抑制胞质分裂(细胞分裂) 并最终导致基底膜细胞死亡。当前提案的总体目标是推进 用NMII小分子抑制剂治疗GBM，通过将计划定位为具有竞争力进入 英国广播公司。R61阶段(第1年)将包括[1]扩大先导化合物SR-561，[2]体外筛选 帮助选择R33期和[3]启动期使用的体内疗效小鼠模型 药物化学部进一步优化SR-561以改善针对特定治疗需求的性能 一种GBM疗法。在成功实现建议书中详细说明的里程碑之后，R33阶段 (第2年和第3年)将涉及[1]通过药物化学进行化合物优化的继续，[2]在体内 用SR-561和优化的类似物[3]进行体外和体内DMPK图谱和[4]化合物的疗效测试 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，将一种NMII小分子抑制剂推向临床，治疗GBM。