SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy

我们的最终目标是开发新的和有效的治疗胶质母细胞瘤，最常见的和致命的 人类脑癌为了实现这一目标，我们建议开发SUMO 1抑制化合物（SMIC 1）， 一种用于胶质母细胞瘤治疗的新型抗癌药物。SUMO 1（small ubiquitin-like modifier-1，小泛素样修饰物-1）是一种小的调控因子。 通过酶促反应与底物蛋白质连接的蛋白质。SUMO 1结合其底物 蛋白质控制底物蛋白质的细胞功能。在我们最近的工作中，我们发现SUMO 1 结合途径在胶质母细胞瘤中过度活跃并驱动癌症进展。为了瞄准这条通路， 我们开发了基于胶质母细胞瘤细胞的SUMO 1试验用于药物筛选，并从中鉴定了SMIC 1 国家癌症研究所药物化合物库在SMIC 1作为抗癌药物的临床前开发工作中， 我们遵循FDA指南，对新抗癌药物进行非临床评价， 和药代动力学（PK），并证明SMIC 1具有可接受的安全范围， 动物中的药代动力学特征。在全身给药中，SMIC 1可通过以下途径快速递送至大脑： 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性激酶6（CDK 6）是这两种蛋白的底物。 SUMO 1和泛素（UB）。SUMO 1-CDK 6缀合阻断CDK 6泛素化和UB介导的CDK 6蛋白表达。 降解，从而稳定CDK 6激酶，通过视网膜母细胞瘤的磷酸化驱动细胞生长 因此，SMIC 1处理阻断SUMO 1-CDK 6缀合并消除CDK 6-RB 1途径。 另一方面，已经开发了靶向CDK 4/6-RB 1通路的CDK 4/6抑制剂，并且它们现在被用于治疗CDK 4/6-RB 1通路。 在癌症治疗的临床上。RB 1缺失和突变发生在约11%的胶质母细胞瘤中，并导致 对CDK 4/6抑制剂的耐药性。相比之下，我们已经证明SMIC 1可以克服电阻 通过抑制各种SUMO 1底物蛋白。本提案的目标是将SMIC 1开发为 一种治疗胶质母细胞瘤的新型抗癌药物。为了实现这一点，我们将首先确定分子 SMIC 1治疗胶质母细胞瘤细胞的作用机制。特别是，我们将研究SMIC 1 处理诱导SUMO 1蛋白的泛素化和降解，并消除SUMO 1结合 人胶质母细胞瘤细胞中的信号通路。接下来，我们将研究SMIC 1的生物活性和药效学 在遗传异质性胶质母细胞瘤细胞中与CDK 4/6抑制剂进行比较，从而确定为什么 SMIC 1处理可以克服RB 1缺失和突变的抗性。最后，我们将评估 SMIC 1使用癌症干细胞培养物和由以下产生的异种移植物模型的治疗功效： 患者的胶质母细胞瘤组织。完成后，这个项目将导致一个新的类抗癌的起源 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.