SUMO Modification and Cancer Therapy

SUMO 改良与癌症治疗

基本信息

批准号：
10396642
负责人：
Yuan Chen
金额：
$ 50.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396642
关键词：
Address Animal Model Antibodies Biochemical Biological Biological Assay CD8-Positive T-Lymphocytes Cancer Patient Cells Cellular Assay Clinical Research Clinical Trials Colorectal Cancer Complex Crystallization Dendritic Cells Drug Kinetics Drug resistance Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Kinetics Enzymes FDA approved Funding Goals Human Immune Immunomodulators Immunotherapy In Vitro Interferon Type I Interferons Intravenous infusion procedures Investigation Knowledge Lead Life Malignant Neoplasms Mediating Medical Methods Modeling Modification Molecular Multienzyme Complexes Mutation Oncogenes Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I/II Clinical Trial Post-Translational Protein Processing Progress Reports Property Proteins Publishing Regulation Resistance Site Solid Neoplasm Stereoisomer Structure Structure-Activity Relationship Sumoylation Pathway T cell response Therapeutic Tumor Immunity Ubiquitin Ubiquitination United States National Institutes of Health analog cancer drug resistance cancer immunotherapy cancer therapy drug discovery drug metabolism experience follow-up high throughput screening human disease improved in vivo inhibitor innovation insight interdisciplinary approach lead optimization neoplastic cell novel resistance mutation response small molecule targeted treatment therapeutic development therapeutic target tumor

项目摘要

Many enzymes catalyzing ubiquitin-like (Ubl) modifications have been identified as targets for the therapeutic development of life-threatening human diseases that lack a cure. However, Ubl modifications are poorly addressed by FDA approved drugs, highlighting the immense potential to exploit this type of post-translational modification to address unmet medical needs. Conjugation of Ubls to target proteins begins by activation of the C-terminus of a Ubl, a step catalyzed by enzymes generally known as activating enzyme or E1. Several E1 enzymes, including the SUMO-activating enzyme (SAE), have been validated as therapeutic targets by animal models and by early phase clinical studies. Our recent discovery of a conserved cryptic site on the SAE provides a paradigm-shifting allosteric approach to inhibit Ubl activating enzymes. In the next funding period, we will further elucidate the mechanism of the structure-activity relationship. Additionally, we will validate that the allosteric inhibition approach we discovered reduces cancer drug resistance for targeting Ubl activating enzymes. Furthermore, we will define the molecular mechanism of how SUMOylation regulates type I IFN expression and validate that SAE inhibition is an effective approach to induce anti-tumor immunity for immune cold colorectal cancers. The proposed studies build on our scientific progress in the previous funding cycle and our more than 20-year experience in studying SUMOylation. The proposed studies are expected to result in long- lasting impacts that will spur innovation in targeting Ubl for therapeutic development and result in new immune therapeutic strategies for immune cold tumors that do not respond to current immune therapies and are high unmet needs, such as colorectal cancers.

许多催化泛素样 (Ubl) 修饰的酶已被确定为无法治愈的危及生命的人类疾病的治疗发展。然而，乌布尔 FDA 批准的药物很难解决修饰问题，凸显了巨大的潜力利用这种类型的翻译后修饰来解决未满足的医疗需求。 Ubl 与靶蛋白的结合是通过激活 Ubl 的 C 末端开始的，这是一个步骤由通常称为活化酶或E1的酶催化。几种E1酶，包括 SUMO 激活酶 (SAE)，已被验证为治疗靶点动物模型和早期临床研究。我们最近发现了一个保守的 SAE 上的神秘位点提供了一种范式转换的变构方法来抑制 Ubl 激活酶。在下一个资助期内，我们将进一步阐明其机制结构-活性关系。此外，我们将验证变构抑制我们发现的方法可降低针对 Ubl 激活的癌症耐药性酶。此外，我们将定义 SUMOylation 的分子机制调节 I 型 IFN 表达并验证 SAE 抑制是一种有效的方法诱导免疫冷性结直肠癌的抗肿瘤免疫力。拟议的研究建立关于我们在上一个资助周期中的科学进展以及我们20多年来的科学进展研究 SUMOylation 的经验。拟议的研究预计将产生长期持久的影响将刺激针对 Ubl 的治疗开发和创新为对免疫冷肿瘤没有反应的新免疫治疗策略目前的免疫疗法和未满足的需求很高，例如结直肠癌。