SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy

SUMO1 抑制化合物作为胶质母细胞瘤治疗的新型抗癌药物

基本信息

批准号：
10054183
负责人：
CHUNHAI Charlie HAO
金额：
$ 38.01万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054183
关键词：
Animals Antineoplastic Agents Automobile Driving Biochemical Reaction Biological Assay Blood - brain barrier anatomy Brain CDC2 gene CDK4 gene Cell Culture Techniques Cell Cycle Cell model Cell physiology Cells Clinic Clinical Treatment Copy Number Polymorphism Data Deletion Mutation Drug Compounding Drug Kinetics Drug Screening Enzyme Inhibition Enzymes Evaluation Genomics Glioblastoma Goals Growth Human Immunohistochemistry In Vitro Legal patent Libraries Link Lysine Malignant Neoplasms Malignant neoplasm of brain Mediating Modeling Modification Molecular Mechanisms of Action Mutation Names Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Phosphorylation Phosphotransferases Polyubiquitin Post-Translational Protein Processing Protein Family Protein Kinase Proteins Recurrence Reporting Resistance Retinoblastoma Protein Safety Site Small Interfering RNA Technology Testing Therapeutic Effect Time Tissues Toxicity Tests Treatment Efficacy Ubiquitin Ubiquitin-Conjugating Enzymes Ubiquitination Work Xenograft Model Xenograft procedure base cancer stem cell cancer therapy cell growth clinical development cyclin-dependent kinase 6 effective therapy enzyme substrate genetic regulatory protein in vivo inhibitor/antagonist knock-down next generation sequencing novel novel anticancer drug preclinical development protein degradation screening self-renewal small molecule tumor progression tumorigenic ubiquitin-protein ligase

项目摘要

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.

我们的最终目标是开发新颖有效的胶质母细胞瘤，最常见和致命的胶质母细胞瘤人脑癌。为了实现这一目标，我们建议将SUMO1抑制化合物（SMIC1）作为一种用于胶质母细胞瘤疗法的新抗癌药。 SUMO1（小泛素样修饰符1）是一个小调节通过酶促反应与底物蛋白相关的蛋白质。 SUMO1的基材结合蛋白质控制底物蛋白的细胞功能。在我们最近的工作中，我们透露了Sumo1 共轭途径在胶质母细胞瘤中过度活跃，并驱动癌症进展。为了达到这一途径，我们已经开发了基于胶质母细胞瘤细胞的SUMO1用于药物筛查，并从 NCI可吸毒复合库。在Smic1作为抗癌药物的临床前发展的努力中，我们遵循了FDA指南，以对新抗癌药进行非临床评估并测试毒性和SMIC1的药代动力学（PK），并证明SMIC1具有可接受的安全保证金动物中可吸毒的PK特征。在系统性管理中，可以通过血脑屏障（BBB）有效地抑制了胶质母细胞瘤异种移植的生长。为了寻找靶蛋白，我们表明Cyclin依赖性激酶-6（CDK6）都是两者的底物 SUMO1和泛素（UB）。 SUMO1-CDK6共轭阻塞CDK6泛素化和UB介导的降解，从而稳定CDK6激酶，以通过视网膜细胞瘤的磷酸化来驱动细胞生长蛋白质1（RB1）;因此，SMIC1处理阻止了SUMO1-CDK6结合并消除CDK6-RB1途径。另一方面，针对CDK4/6-RB1途径的CDK4/6抑制剂已经开发在癌症疗法的诊所中。 RB1缺失和突变发生在约11％的胶质母细胞瘤中，并导致对CDK4/6抑制剂的抗癌性。相比之下，我们已经表明SMIC1可以克服电阻通过抑制各种SUMO1底物蛋白。该提议的目的是将SMIC1作为一种用于治疗胶质母细胞瘤的新抗癌药。为此，我们将首先确定分子 SMIC1在治疗胶质母细胞瘤细胞中的作用机制。特别是，我们将研究SMIC1如何治疗诱导SUMO1蛋白的泛素化和降解并废除SUMO1共轭人胶质母细胞瘤细胞中的途径。接下来，我们将检查SMIC1的生物活性和药效学与遗传异源性胶质母细胞瘤细胞中的CDK4/6抑制剂相比，因此确定了为什么 SMIC1处理可以克服RB1缺失和突变的抗性。最后，我们将评估使用癌症干细胞培养物和异种移植模型对SMIC1的治疗功效患者的胶质母细胞瘤组织。完成后，该项目将导致新阶级抗癌的起源用于胶质母细胞瘤患者临床治疗的药物。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.

DOI：
10.1126/scitranslmed.abh1486
发表时间：
2021-10-13
期刊：
SCIENCE TRANSLATIONAL MEDICINE
影响因子：
17.1
作者：
Bellail, Anita C.;Jin, Hong Ri;Lo, Ho-Yin;Jung, Sung Han;Hamdouchi, Chafiq;Kim, Daeho;Higgins, Ryan K.;Blanck, Maximilian;le Sage, Carlos;Cross, Benedict C. S.;Li, Jing;Mosley, Amber L.;Wijeratne, Aruna B.;Jiang, Wen;Ghosh, Manali;Zhao, Yin Quan;Hauck, Paula M.;Shekhar, Anantha;Hao, Chunhai
通讯作者：
Hao, Chunhai