Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma

项目摘要 一个显著未满足需求的领域是胶质母细胞瘤（GBM）的治疗，胶质母细胞瘤是一种侵袭性、快速生长和致命的恶性肿瘤。 占所有脑肿瘤的15%。如果不治疗，GBM通常在三个月内致命。 而且，由于高复发率，目前的护理标准，包括安全的最大限度的肿瘤切除， 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 增殖定义了GBM的表型，而GBM细胞只做一种或另一种。然而，阻挡 侵袭刺激增殖，反之亦然，这意味着理想的治疗靶点必须满足2个标准： 1)驱动侵袭和增殖，以及2）在抑制时阻断两者，即使它们的途径是活跃的。 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是 来满足这些标准。然而，这项研究的转化潜力受到缺乏一个 临床安全，CNS渗透性NMII小分子抑制剂。在药物化学工作的支持下， 蓝图神经治疗学（BPN）奖，临床安全的小分子NMII变构衍生物 抑制剂Blebbistatin作为药物成瘾治疗正在开发中。发展这类 化合物已经使初步的原理验证研究表明，这些NMII抑制剂显着 改善侵袭性GBM小鼠模型的存活率，可能通过抑制胞质分裂（细胞分裂） 最终导致GBM细胞死亡本提案的总体目标是促进以下方面的潜力： 通过将所述程序定位为竞争性进入NMII小分子抑制剂治疗GBM， 的BPN。R61阶段（第1年）将包括[1]先导化合物SR-561的规模扩大，[2]体外筛选 GBM细胞系，以帮助选择用于R33期和[3]启动期的体内有效性鼠模型 进一步优化SR-561，以改善针对特定治疗需求的特性 GBM的治疗。在成功实现提案中详述的里程碑后，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和优化的类似物进行的功效测试，[3]体外和体内DMPK分析和[4]化合物 耐受性测试。预计拟议的工作将为成功进入建立必要的参数 BPN计划，以推进NMII小分子抑制剂用于临床治疗GBM。

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.