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.

项目概要细胞先天免疫传感器，例如 STING（干扰素基因刺激物），已进化为检测细胞的微生物感染 (1-3)。途径并被环状二核苷酸 (CDN) 激活，例如由或者，STING 可以被环 GMP-AMP (cGAMP) 激活。由细胞 cGAMP 合酶 cGAS (MB21D1) 与异常胞质 dsDNA 结合后产生物种，其中可能包括微生物 DNA 或从细胞核泄漏的自身 DNA (4)。使 STING 能够激活 I 型干扰素 (IFN) 和促炎细胞因子的产生，从而促进适应性免疫 (3) 除了对于预防微生物感染至关重要之外，STING 也是如此。信号传导已被证明对于促进强大的抗肿瘤免疫调节至关重要。免疫系统刺激抗肿瘤细胞毒性 T 细胞反应被证明是治疗癌症的有效方法。例如，基于合成 CDN 的 STING 激动剂已被用于治疗多种癌症。显示可能通过刺激 APC 发挥有效的抗肿瘤特性，目前正在第一阶段进行评估然而，此类 CDN 非常不稳定，并且在治疗癌症时不会发挥有效的活性。这限制了它们的使用/评估为瘤内和口服给药。描述了新一代新型小型 STING 激动剂，可激活 STING 信号传导，似乎优于现有的 CDN，用于评估抗肿瘤治疗策略。 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。