Explore the therapeutic potential of small-molecule immune modulators

探索小分子免疫调节剂的治疗潜力

• 批准号: 10526428
• 负责人: CHUO CHEN
• 金额: $ 38.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526428
• 关键词: ADME Study; Alkylation; Antibodies; Antineoplastic Agents; Binding; Binding Proteins; CD8-Positive T-Lymphocytes; Cause of Death; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemotherapy and/or radiation; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Dinucleoside Phosphates; Effectiveness; Evaluation; Future; Gene Activation; Goals; Heart Diseases; Human; Immune Targeting; Immune response; Immune system; Immunity; Immunologic Adjuvants; Immunologic Stimulation; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Innate Immune System; Investigational Drugs; Knowledge; Literature; Lymphatic; Lymphatic System; Malignant Neoplasms; Mannose; Maps; Metabolic; Methods; Modality; Modification; Mus; Natural Immunity; Patients; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Property; Proteins; Proteomics; Published Comment; Publishing; Research; Risk; Risk Reduction; Role; Safety; Second Messenger Systems; Site; Stimulator of Interferon Genes; System; Therapeutic; Time; Toxic effect; Triglycerides; Tumor Antigens; Tumor Immunity; Tumor Promotion; Work; absorption; analog; anti-PD-L1 antibodies; anti-cancer; cancer immunotherapy; cancer therapy; comparative efficacy; design; drug development; fighting; immune checkpoint; immune checkpoint blockade; immune stimulatory agent; improved; in vivo; interest; novel; novel therapeutic intervention; programmed cell death ligand 1; programs; response; small molecule; synergism; systemic inflammatory response; targeted delivery; tumor; tumor microenvironment

The overarching goal of our research program is to facilitate the development small-molecule drugs. The focus of this study is to explore the therapeutic potential of the cyclic dinucleotide class of immunopotentiators in cancer. Cancer is the second leading cause of death, contributing to 22.5% of total deaths in the US. Recently, immune checkpoint blockade has emerged as a powerful treatment modality for cancer, showing remarkable efficacy and response rate. Unlike the traditional radiation or chemotherapies, it utilizes our bodies’ own immune system to fight cancer. However, many patients do not have sufficient immunity to benefit from this new treatment strategy. Our team has recently identified cGAMP to be the endogenous small-molecule that activates the innate immune system and demonstrated its antitumor activity in mice. Based on this work, several synthetic analogs have been developed by pharmaceutical companies to mimic this natural immunopotentiator. The accumulated effort has led to two Phase I clinical trials to evaluate the safety and tolerance of cGAMP analogs in human. Despite the rapid progress, the full functional profile of cGAMP is still not clear. In this project, we will establish a proteomic approach to extensively map drug-protein interactions for cGAMP and its metabolically stable analogs including the investigational drug MIW815. This work will help shed lights on the potential new functions of cGAMP and the potential off-target effects of synthetic cyclic dinucleotides. Additionally, we believe that selective activation of a specific group of dendritic cells by cGAMP or its analogs will help reduce the risk of systemic inflammation, the major concern of the immune stimulation therapies. We will thus develop a conjugation strategy for site-specific delivery of cGAMP to improve efficacy, reduce toxicity, and help understand the roles of dendritic cells at different sites in anticancer immunity. Overall, the results of this study will inform future development of cGAMP analogs for their safe use in human and provide information on the role of innate immunity in cancer.

我们研究计划的首要目标是促进小分子药物的开发。重点 本研究的目的是探索环二核苷酸类免疫增强剂在治疗 癌癌症是第二大死亡原因，占美国总死亡人数的22.5%。最近， 免疫检查点阻断已经成为癌症的强大治疗方式，显示出显著的 疗效和反应率。与传统的放疗或化疗不同，它利用我们身体自身的能力 免疫系统对抗癌症。然而，许多患者没有足够的免疫力，无法从中获益 新的治疗策略。我们的团队最近发现cGAMP是内源性小分子， 激活先天免疫系统，并在小鼠中证明其抗肿瘤活性。在此基础上， 制药公司已经开发了几种合成类似物来模仿这种天然的 免疫增强剂。累积的努力导致了两个I期临床试验，以评估安全性和 人中cGAMP类似物的耐受性。尽管进展迅速，但cGAMP的完整功能概况仍然是未知的。 不清楚在这个项目中，我们将建立一个蛋白质组学的方法来广泛映射药物-蛋白质相互作用， cGAMP及其代谢稳定的类似物，包括研究药物MIW 815。这项工作将有助于 揭示了cGAMP的潜在新功能和合成环腺苷酸的潜在脱靶效应。 二核苷酸。此外，我们认为cGAMP选择性激活一组特定的树突状细胞， 或其类似物将有助于降低全身炎症的风险， 治疗因此，我们将开发用于cGAMP的位点特异性递送的缀合策略以提高功效， 降低毒性，并有助于了解树突状细胞在抗癌免疫中不同部位的作用。总的来说， 本研究的结果将为cGAMP类似物在人类中的安全使用提供信息， 提供关于先天免疫在癌症中的作用的信息。

项目成果

Avoid the trap: Targeting PARP1 beyond human malignancy.

避免陷阱：针对人类恶性肿瘤以外的PARP1。

• DOI: 10.1016/j.chembiol.2021.02.004
• 发表时间: 2021-04-15
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Kim C;Chen C;Yu Y
• 通讯作者: Yu Y

A phosphine-based redox method for direct conjugation of disulfides.

• DOI: 10.1039/d2cc04967h
• 发表时间: 2022-11-08
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Lu, Yong;You, Lin;Chen, Chuo
• 通讯作者: Chen, Chuo

Orthogonal Hydroxyl Functionalization of cGAMP Confers Metabolic Stability and Enables Antibody Conjugation.

• DOI: 10.1021/acscentsci.3c01122
• 发表时间: 2023-12-27
• 期刊: ACS CENTRAL SCIENCE
• 影响因子: 18.2
• 作者: Lu, Yong;You, Lin;Li, Liping;Kilgore, Jessica A.;Liu, Shun;Wang, Xiaoyu;Dai, Yuanwei;Wei, Qi;Shi, Heping;Han, Lei;Sun, Lijun;Chen, Zhijian J.;Zhang, Xuewu;Williams, Noelle S.;Chen, Chuo
• 通讯作者: Chen, Chuo