SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy

我们的最终目标是开发新的有效治疗胶质母细胞瘤的方法，胶质母细胞瘤是最常见和最致命的 人类脑癌。为了实现这一目标，我们建议将SUMO1抑制化合物(SMIC1)开发为 一种治疗胶质母细胞瘤的抗癌新药。SUMO1(小泛素样修饰物-1)是一种小型调节性蛋白 通过酶反应与底物蛋白质相连的蛋白质。其底物的SUMO1偶联 蛋白质控制底物蛋白质的细胞功能。在我们最近的工作中，我们揭示了SUMO1 结合途径在胶质母细胞瘤中过度活跃，并推动肿瘤的进展。为了瞄准这条路径， 我们已经建立了基于胶质母细胞瘤细胞的SUMO1药物筛选方法，并从 NCI的可用药化合物图书馆。在SMIC1作为抗癌药物的临床前开发工作中， 我们遵循了fda的指南，对新的抗癌药物进行了非临床评价并进行了毒性试验。 和SMIC1的药代动力学(PK)，表明SMIC1具有可接受的安全裕度和 在动物身上有可吸毒的PK特征。在全身给药中，SMIC1可以通过以下途径迅速传递到大脑 血脑屏障(BBB)，并有效地抑制胶质母细胞瘤异种移植生长。 在寻找靶蛋白的过程中，我们发现细胞周期蛋白依赖的激酶-6(Cdk6)是两者的底物。 SUMO1和泛素(UB)。SUMO1-CDK6结合阻断CDK6泛素化及UB介导的 降解，从而稳定CDK6激酶，通过磷酸化视网膜母细胞瘤来驱动细胞生长 蛋白-1(RB1)；因此，SMIC1处理阻断了SUMO1-CDK6的结合，并消除了CDK6-RB1途径。 另一方面，针对CDK4/6-RB1途径的CDK4/6抑制剂已经被开发出来，它们现在正在 接受癌症治疗的临床医生。Rb1缺失和突变发生在大约11%的胶质母细胞瘤中，并导致 肿瘤对CDK4/6抑制剂的耐药性。相反，我们已经证明SMIC1可以克服阻力 通过抑制各种SUMO1底物蛋白。这项建议的目标是将SMIC1发展为 治疗胶质母细胞瘤的抗癌新药。为了实现这一点，我们将首先确定分子 SMIC1在胶质母细胞瘤细胞治疗中的作用机制我们将特别研究SMIC1如何 治疗诱导SUMO1蛋白泛素化和降解并取消SUMO1结合 人脑胶质母细胞瘤细胞中的通路。接下来，我们将研究SMIC1的生物活性和药效学 与CDK4/6抑制剂在基因异质性胶质母细胞瘤细胞中的比较，从而确定为什么 SMIC1处理可以克服RB1缺失和突变的抗性。最后，我们将评估 SMIC1在肿瘤干细胞培养和异种移植模型中的治疗作用 患者的胶质母细胞瘤组织。该项目完成后，将催生一种新的抗癌药物。 用于临床治疗胶质母细胞瘤患者的药物。

Our ultimate goal is to develop novel and effective treatments of glioblastoma, the most common and lethal human brain cancer. To achieve this goal, we propose to develop the SUMO1 inhibition compound (SMIC1) as a new anticancer drug for glioblastoma therapy. SUMO1 (small ubiquitin-like modifier-1) is a small regulatory protein that is linked to substrate proteins through enzymatic reactions. SUMO1 conjugation of its substrate proteins controls the cellular function of substrate proteins. In our recent work, we have revealed that SUMO1 conjugation pathway is overactive in glioblastoma and drives the cancer progression. To target this pathway, we have developed glioblastoma cell-based SUMO1 assays for drug screening and identified the SMIC1 from the NCI drugable compound library. In the efforts of preclinical development of SMIC1 as an anticancer drug, we have followed the FDA guidance for nonclinical evaluation of new anticancer agents and tested the toxicity and pharmacokinetics (PK) of SMIC1 and demonstrated that SMIC1 has an acceptable safety margin and drugable PK features in animals. In systemic administration, SMIC1 can be quickly delivered to brains through the blood brain barrier (BBB) and effectively inhibits glioblastoma xenograft growth. In search of target proteins, we have shown that cyclin-dependent kinase-6 (CDK6) is a substrate of both SUMO1 and ubiquitin (UB). SUMO1-CDK6 conjugation blocks CDK6 ubiquitination and the UB-mediated degradation and thus stabilizes CDK6 kinase for driving cell growth through phosphorylation of retinoblastoma protein-1 (RB1); thus, SMIC1 treatment blocks SUMO1-CDK6 conjugation and eliminates CDK6-RB1 pathway. On the other hand, CDK4/6 inhibitors have been developed targeting CDK4/6-RB1 pathway and they are now in clinic for cancer therapies. RB1 deletion and mutation occurs in about 11% glioblastomas and results in the cancer resistance to CDK4/6 inhibitors. In contrast, we have shown that SMIC1 can overcome the resistance through inhibition of various SUMO1 substrate proteins. The objective of this proposal is to develop SMIC1 as a new anticancer drug for treatment of glioblastomas. To achieve this, we will first determine the molecular mechanisms of action of SMIC1 in treatment of glioblastoma cells. In particular, we will examine how SMIC1 treatment induces the ubiquitination and degradation of SUMO1 protein and abolishes SUMO1 conjugation pathway in human glioblastoma cells. Next, we will examine the bioactivity and pharmacodynamics of SMIC1 in comparison with CDK4/6 inhibitors in genetically heterogenous glioblastoma cells and thus determine why SMIC1 treatment can overcome the resistance of RB1 deletion and mutation. Finally, we will evaluate the therapeutic efficacy of SMIC1 using the cancer stem cell cultures and xenograft models generated from patients' glioblastoma tissues. Upon completion, this project will lead to the genesis of a new class anticancer drug for clinical treatment of glioblastoma patients.