A novel small molecule tricyclic series of STING activators was designed, synthesized and evaluated for human STING activity. These STING agonists were optimized from an initial set of structures with low potency through iterative cycles of design, synthesis and biological evaluation to yield compounds with potent human STING activity. The binding and functional properties of 68, an exemplar from the series were determined. Further, while 68 activated major variants of human STING it did not activate murine STING. Treatment of human PBMCs led to pathway engagement and the release of pro-inflammatory cytokines. When administered intra-tumorally, 68 caused robust retardation in the growth of MCA205 mouse fibrosarcoma tumors in human STING knock-in mice.

2024-09-01·Clinical Advances in Hematology & Oncology

STING activators in cancer care.

Article

作者: Sweis, Randy F

2023-12-01·European journal of medicinal chemistry

Discovery of novel amidobenzimidazole derivatives as orally available small molecule modulators of stimulator of interferon genes for cancer immunotherapy

Article

作者: Lee, Hyelim ; Choo, Hyunah ; Jeon, Min Jae ; Jo, Seongman ; Lee, Sanghee ; Kang, Miso ; Lee, Joo-Youn ; Kim, Hyejin ; Song, Gyu Yong ; Jeong, Jeong Hyun ; Jeong, So Hyeon

Stimulator of interferon genes (STING) agonists show promise as immunomodulatory agents for cancer therapy. In this study, we report the discovery of a novel orally available STING agonist, SAP-04, that exhibits potent immunomodulatory effects for cancer therapy. By optimizing the amidobenzimidazole core with various pyridine-based heterocyclic substituents, we identified a monomeric variant that displayed more efficient STING agonistic activity than the corresponding dimer. SAP-04 efficiently induced cytokine secretion related to innate immunity by directly binding of the compound to the STING protein, followed by sequential signal transduction for the STING signaling pathway and type I interferon (IFN) responses. Further pharmacological validation in vitro and in vivo demonstrated the potential utility of SAP-04 as an immunomodulatory agent for cancer therapy in vivo. The in vivo anticancer effect was observed in a 4T1 breast tumor syngeneic mouse model through oral administration of the compound. Our findings suggest a possible strategy for developing synthetically accessible monomeric variants as orally available STING agonists.

100 项与 SAP-04 相关的药物交易

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