Abstract 6983: Innovative oral STING agonists for cancer therapy

Abstract STING, functioning as an adaptor protein, plays a pivotal role in the induction of type I interferons (IFN) and pro-inflammatory cytokines subsequent to the detection of cytosolic DNA. The development of a non-nucleotide STING agonist amenable to oral administration holds the promise of expanding the clinical utility of STING agonists among cancer patients. Leveraging computer-aided drug design strategies, a cohort of non-nucleotide STING agonists endowed with oral antitumor activities was meticulously designed and synthesized, with the overarching goal of exploring uncharted druggability domains. Among the array of investigated compounds, ZSSW21040164 manifested remarkable IFN-β (Interferon-β) activities within the tumor microenvironment. Rigorous experimental validation unequivocally demonstrated that ZSSW21040164 activates the downstream signaling cascade of STING via a STING-dependent modality. Moreover, ZSSW21040164 exhibited favorable pharmacokinetic (PK) characteristics, notably high oral bioavailability. In murine tumor models bearing H22, MC38, and CT-26 tumors, oral administration of ZSSW21040164 was well-tolerated and had a significant anti-tumor effect with more tumors achieved complete remission, which accompanied by the establishment of durable antitumor immunity. Notably, when ZSSW21040164 was co-administered with a fully murinized anti-mouse PD-1 antibody, the antitumor efficacy of single-agent therapy was substantially augmented. Collectively, these findings strongly suggest that ZSSW21040164 harbors considerable potential for development as an efficacious antitumor agent, warranting further preclinical and clinical investigations. Within this work, a series of aryl-fused heterocycles STING agonists with significant potency towards STING were investigated. The investigation comprised multiple aspects, namely, the identification methodology, pharmacokinetic (PK) properties determination, evaluation of in vitro and in vivo antitumor activities, and the elucidation of relevant structure-activity relationships (SARs). ZSSW21040164, an orally available human STING agonist, emerged as a crucial finding. It is anticipated that this compound will serve as a valuable reference for the discovery and design of human STING agonists suitable for systemic administration in a clinical setting, thereby contributing to the advancement of cancer therapeutics. Citation Format: Zhiyong Qin, Limin Jia, Chengyu Yang, Chuanyun Yu, Yang Lv, Yujie Wang, Pan Li. Innovative oral STING agonists for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6983.