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

• 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
• 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

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，如STING（干扰素基因刺激物），已经进化为 检测细胞的微生物感染（1-3）。STING控制有效的细胞溶质DNA刺激的先天免疫 通过环二核苷酸（CDN）激活，如由细胞分泌的环二GMP和环二AMP。 感染后的细胞内细菌。或者，STING可以通过环GMP-AMP（cGAMP）激活。 由细胞cGAMP合酶cGAS（MB 21 D1）在与异常胞质dsDNA结合后产生 物种，其可以包括微生物DNA或从细胞核泄漏的自身DNA（4）。与CDN关联 使STING能够激活I型干扰素（IFN）和促炎细胞因子的产生， 促进适应性免疫（3）。除了对防止微生物感染至关重要外，STING 已经显示信号传导对于促进稳健的抗肿瘤免疫是必需的。调控 免疫系统刺激抗肿瘤细胞毒性T细胞反应被证明是一种强有力的方法， 有效治疗多种癌症。例如，基于合成CDN的STING激动剂已经被广泛应用于临床。 显示可能通过刺激APC发挥有效的抗肿瘤特性，目前正在进行I期评估 治疗癌症的试验然而，这样的CDN是高度不稳定的，并且当使用时不发挥有效的活性。 系统地给予。这限制了它们在肿瘤内和口服给药中的使用/评价。这里我们 描述了激活STING信号传导的新一代新的小STING激动剂，其表现出优于STING激动剂的上级特性。 现有的CDN，用于评估抗肿瘤治疗策略。这些化合物是由 STINGINN LLC，总部设在迈阿密，与佛罗里达州迈阿密大学医学院合作。