Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy |
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| Institution: | 1. Department of Immunology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv., Houston 77030, TX, USA;2. The University of Texas MD Anderson UTHealth Graduate School of Biochemical Sciences, Immunology Program, 1515 Holcombe Blv., Houston 77030, TX, USA;3. WuXi AppTec (Wuhan) Co., Ltd., 666 Gaoxin Road, Wuhan East Lake High-tech Development Zone, Hubei 430075, China;4. Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv., Houston 77030, TX, USA;1. Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Université libre de Bruxelles, Boulevard du Triomphe, 1050 Brussels, Belgium;2. Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;1. College of Pharmaceutical Science, Soochow University, Suzhou 215123, China;2. Center for Drug Design, University of Minnesota, MN 55455, USA;3. MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Institute of Infectious Disease and Molecular Medicine and Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa;1. Department of Integrative Oncology, BC Cancer Agency, Vancouver, Canada;2. Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada;3. These authors contributed equally to this work;1. Aduro Biotech, Inc., Berkeley, CA 94710, USA;2. Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA;3. Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA;1. Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, PA, USA;2. Department of Gastroenterology, Henan Provincial People''s Hospital, Zhengzhou University, Zhengzhou, Henan, China;3. Microbiology and Immunology Graduate Program, Drexel University College of Medicine, Philadelphia, PA, USA;4. Artificial Liver Center, Beijing You''an Hospital, Capital Medical University, Beijing, China;5. Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA |
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| Abstract: | Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-β) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds. |
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| Keywords: | STING agonists Cyclic dinucleotide Immune response T-cell priming Phosphorothioate esters |
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