Affiliation:
1. Division of Antitumor Pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
2. Shanghai Frontiers Science Center of Drug Target Identification and Delivery College of Pharmaceutical Sciences National Key Laboratory of Innovative Immunotherapy Shanghai Jiao Tong University Shanghai China
3. Chemical Biology Research Center School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou China
4. School of Life Science and Technology ShanghaiTech University Shanghai China
5. University of Chinese Academy of Sciences Beijing China
6. Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery Yantai China
Abstract
AbstractBackgroundStimulator of interferon genes (STING) has emerged as a crucial and promising target in tumor immunotherapy in recent years. Its agonists play a vital role in activating both innate and adaptive immune responses to combat cancer. Currently, STING agonists are primarily administered through intratumoral or intravenous injection, with only a few could be administered by orally. Therefore, orally available STING agonists are urgently needed to be developed.Approach and resultsBased on previous structure‐activity relationship (SAR) studies, we made a structure modification to MSA‐2 by replacing the carbonyl group with a difluoromethylene to get a new compound 202 (C202) that exhibited better plasma exposure and oral bioavailability than MSA‐2. Thus, we conducted extensive pharmacological evaluations to understand its effects. C202 demonstrated the ability to activate various human STING isoforms and murine STING protein, showcasing a potent and specific activation of the STING signalling pathway at cellular level. In diverse immunocompetent mouse models representing both ‘cold’ and ‘hot’ tumors, C202, whether administered intratumorally or orally, displayed broad‐spectrum anti‐tumor activity. Encouragingly, it induced complete tumor regression in several tumor models of mice and stimulated immune memory effects, contributing to long‐term immune response against cancer. Additionally, our investigations into the impact of C202 on the tumor microenvironment found that it enhanced the anti‐tumor response of both innate and adaptive immune systems, bolstering the immune‐mediated fight against tumors. Furthermore, we made an intriguing observation regarding C202's synergistic effects. It was found to enhance the anti‐tumor activity of chemotherapy drug gemcitabine and the angiogenesis inhibitor AL3810, which provide potential combination therapies in future translational studies.ConclusionsOur research highlights C202 as a novel STING agonist with durable anti‐tumor activity that can be administered orally, presenting a promising candidate for cancer immunotherapy.
Funder
National Natural Science Foundation of China
Science and Technology Commission of Shanghai Municipality
National Science and Technology Major Project
National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology