Abstract 4475: Discovery of an oral tricyclic STING agonist with superior pharmacokinetic properties and potent in vivo efficacy

Abstract Stimulator of interferon genes (STING) plays a pivotal role in regulating immune microenvironment for cancer immunotherapy. However, the use of most STING agonists has been hindered by the necessity for intra-tumoral or intravenous administration, underscoring the challenge in developing an orally bioavailable STING agonist with favorable pharmacokinetic (PK) properties. In this study, we discovered oral STING agonists featuring a novel tricyclic benzo[4,5]thieno[2,3-c]pyrrole-1,3-dione scaffold, thus achieving both superior PK properties and potent in vivo efficacy. Our lead compound, ZSA-51, exhibited nanomolar cellular STING activation activity (EC50 = 100 nM) in THP1 cells, surpassing the reported oral STING agonist MSA-2 by 32-fold (EC50 = 3200 nM). Furthermore, ZSA-51 demonstrated superior PK properties with an oral bioavailability of 49%, and robust in vivo antitumor activity both in colon and pancreatic cancers model upon oral administration. Notably, ZSA-51 displayed preferential distribution to the lymph nodes and spleen, enhancing its systemic immune-stimulating effects. The specificity of ZSA-51 was further confirmed by a comparison with a negative control compound (ZSA-52NC2) that was unable to stimulate in vitro and in vivo STING activity. Molecular docking and MD simulation confirmed that the active form of ZSA-51 stably bound to STING dimer with validated hydrogen bond network. Taken together, our findings suggest ZSA-51 as a promising oral STING agonist characterized by superior PK properties and potent in vivo efficacy, holding potential for future development for cancer immunotherapy. Citation Format: Hong-Yi Zhao, Zhongwei Liu, Shuai Mao, Miao He, Meilin Wang, Bo Wen, Wei Gao, Duxin Sun. Discovery of an oral tricyclic STING agonist with superior pharmacokinetic properties and potent in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4475.