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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针对胶质母细胞瘤的新颖有效的治疗方法，胶质母细胞瘤是最常见和致命的疾病人类脑癌。为了实现这一目标，我们建议开发 SUMO1 抑制化合物（SMIC1）：一种用于治疗胶质母细胞瘤的新抗癌药物。 SUMO1（小泛素样修饰剂-1）是一种小型调节剂通过酶促反应与底物蛋白连接的蛋白质。 SUMO1 与其底物的结合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 SUMO1 接合途径在胶质母细胞瘤中过度活跃并驱动癌症进展。为了瞄准这条途径，我们开发了基于胶质母细胞瘤细胞的 SUMO1 检测方法用于药物筛选，并从其中鉴定出 SMIC1 NCI 可药物化合物库。在SMIC1作为抗癌药物的临床前开发的努力中，我们遵循FDA关于新抗癌药物非临床评价的指南并测试了毒性和 SMIC1 的药代动力学（PK），并证明 SMIC1 具有可接受的安全裕度和动物体内可药物的 PK 特征。在全身给药中，SMIC1可以通过血脑屏障（BBB）并有效抑制胶质母细胞瘤异种移植物的生长。在寻找靶蛋白时，我们发现细胞周期蛋白依赖性激酶 6 (CDK6) 是两者的底物 SUMO1 和泛素 (UB)。 SUMO1-CDK6 缀合可阻断 CDK6 泛素化和 UB 介导的降解，从而稳定 CDK6 激酶，通过视网膜母细胞瘤磷酸化驱动细胞生长蛋白质-1 (RB1);因此，SMIC1 治疗可阻断 SUMO1-CDK6 结合并消除 CDK6-RB1 通路。另一方面，针对CDK4/6-RB1通路的CDK4/6抑制剂已被开发出来，现已上市在临床上用于癌症治疗。约 11% 的胶质母细胞瘤中发生 RB1 缺失和突变，并导致癌症对 CDK4/6 抑制剂的耐药性。相比之下，我们已经证明 SMIC1 可以克服阻力通过抑制各种 SUMO1 底物蛋白。本提案的目标是将 SMIC1 发展为一种用于治疗胶质母细胞瘤的新抗癌药物。为了实现这一点，我们首先要确定分子 SMIC1治疗胶质母细胞瘤细胞的作用机制。我们将特别研究 SMIC1 如何治疗诱导 SUMO1 蛋白泛素化和降解并消除 SUMO1 结合人胶质母细胞瘤细胞中的途径。接下来我们将考察SMIC1的生物活性和药效学与遗传异质性胶质母细胞瘤细胞中的 CDK4/6 抑制剂进行比较，从而确定原因 SMIC1治疗可以克服RB1缺失和突变的抵抗力。最后，我们将评估使用癌症干细胞培养物和异种移植模型生成的 SMIC1 的治疗效果患者的胶质母细胞瘤组织。完成后，该项目将导致新型抗癌药物的诞生临床治疗胶质母细胞瘤患者的药物。

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