Human specific STING agonists for the treatment of cancer

用于治疗癌症的人类特异性 STING 激动剂

基本信息

批准号：
10759593
负责人：
JEONGHYUN AHN
金额：
$ 39.98万
依托单位：
STINGINN, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759593
关键词：
Adjuvant Agonist Antineoplastic Agents Antitumor Response Bacteria Barbering Binding Biological Assay CAR T cell therapy Cell Nucleus Cells Chemicals Clinical Trials Collaborations Cyclic GMP Cytotoxic T-Lymphocytes DNA Data Dinucleoside Phosphates Drug Kinetics Endoplasmic Reticulum Epigenetic Process Evaluation Event Exhibits Family Gene Activation Generations Genetic Transcription Golgi Apparatus Half-Life Host Defense Human IRF3 gene Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunologic Stimulation Immunotherapy Infection Inflammatory Innate Immune System Interferon Type I Intravenous Knock-in Laboratories Lead Luciferases MDA MB 231 Malignant Neoplasms Modeling Mus Nucleic Acids Oral Administration Pathway interactions Periodicity Pharmaceutical Preparations Predisposition Production Property Proteins Radiation Route Safety Signal Transduction Stimulator of Interferon Genes T cell response T-Lymphocyte TANK-binding kinase 1 Therapeutic Toll-like receptors Tumor Immunity Universities Vaccines adaptive immunity analog anti-PD-1 antimicrobial drug antitumor agent cancer cell cancer therapy chemotherapeutic agent clinical development cytokine design dosage ds-DNA effective therapy efficacy evaluation experimental study high throughput screening immunoregulation in vivo innate immune pathways medical schools melanoma microbial novel pathogen pembrolizumab phase I trial phosphoric diester hydrolase programmed cell death protein 1 screening sensor small molecule transcription factor triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell (1-3). STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus (4). Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity (3). Aside from being critical for the protection against microbial infection, STING signaling has been shown to be essential for facilitating robust anti-tumor immunity. Regulation of the immune system to stimulate anti-tumor cytotoxic T cell responses is proving to be a powerful approach for the effective treatment of a variety of cancers. For example, STING agonists, based on synthetic CDNs, have been shown to exert potent anti-tumor properties likely by stimulating APCs and are now being evaluated in Phase I trials for the treatment of cancer. However, such CDNs are highly labile and do not exert potent activity when given systemically. This has limited their use/evaluation to intratumoral and oral administration. Here, we describe a new generation of novel small STING agonists that activate STING signaling, that appear superior to existing CDN’s, for evaluation in anti-tumor therapeutic strategies. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.

项目摘要细胞先天免疫传感器，例如刺激（干扰素基因的刺激剂），已经演变为检测细胞的微生物感染（1-3）。 STING控制潜在的胞质DNA刺激的先天免疫途径并被环状二核苷酸（CDN）激活感染后细胞内细菌。另外，可以通过环状GMP-AMP（CGAMP）激活刺激与异常胞质dsDNA相关后，由细胞CGAMP合酶CGA（MB21D1）产生物种，其中可能包括从细胞核中泄漏的微生物DNA或自动-DNA（4）。与CDN的关联使Sting能够激活I型干扰素（IFN）和促炎细胞因子的产生，这促进适应性免疫学（3）。除了保护微生物感染至关重要之外，信号已被证明对于促进可靠的抗肿瘤免疫至关重要。调节刺激抗肿瘤细胞毒性T细胞反应的免疫系统被证明是一种强大的方法有效治疗各种癌症。例如，基于合成CDN的刺激激动剂已经是证明可以通过刺激APC发挥潜在的抗肿瘤特性，现在正在I期评估癌症治疗的试验。但是，此类CDN具有高标签，并且在系统地给予。这将其使用/评估限制在肿瘤内和口服。在这里，我们描述一种新一代的新型小刺痛激动剂，它们激活刺激信号，似乎优于现有的CDN，用于评估抗肿瘤治疗策略。这些化合物是由 Stinginn LLC，总部位于迈阿密，与佛罗里达州迈阿密大学医学院合作。