权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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）修饰的酶已被鉴定为靶点，对危及生命但无法治愈的人类疾病的治疗进展。然而，Ubl FDA批准的药物对修饰的处理很差，突出了巨大的潜力，利用这种类型的翻译后修饰来解决未满足的医疗需求。 Ubl与靶蛋白的缀合通过激活Ubl的C末端开始，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。我们最近发现了一种保守的 SAE上的隐蔽位点提供了一种范式转换的变构方法来抑制Ubl 活化酶在下一个拨款期内，我们会进一步阐明构效关系。此外，我们将验证变构抑制我们发现的一种方法可以降低针对Ubl激活的癌症耐药性。内切酶此外，我们将定义SUMO化的分子机制，调节I型IFN的表达，并证实SAE抑制是一种有效的方法，诱导免疫性冷结直肠癌抗肿瘤免疫。拟议的研究建立我们在上一个资助周期的科学进展和我们20多年来的研究SUMO化的经验。预计拟议的研究将产生长期的- 持久的影响，将刺激创新，针对Ubl的治疗开发，导致新的免疫治疗策略的免疫冷肿瘤，不响应目前的免疫疗法和高度未满足的需求，如结直肠癌。