Abstract 4882: LCB39, a novel systemically deliverable STING agonist with strong preclinical activity and tolerability

Abstract Direct STING activation with STING agonists is very effective in tumor control through Type I IFN responses in preclinical animal models. However, STING agonist therapeutics have faced major hurdles in clinical success due to limited bioavailability and suboptimal efficacy within tolerable doses. Here, we introduced LCB39, a novel non-CDN STING agonist small molecule currently at the preclinical development. LCB39 was intentionally generated toward the characteristics of lower cell permeability while maintaining its direct STING binding potency to improve systemic tolerability. Compared to diABZi compounds, such as GSK#3 or XMT-1616, LCB39 had about 100-fold lower THP-1 reporter activity with about 5-fold lower direct binding potency. As expected, LCB39 dramatically improved normal cell cytotoxicity to hPBMCs and HSCs. In addition, LCB39 did not induce stromal cell activation nor cell death. In contrast to the in vitro potency, LCB39 strongly promoted tumor growth suppression in a dose-dependent manner in several syngeneic mouse models. Mechanistically, LCB39 had a tumor-targeting and retention activity and promoted immune priming of tumor tissue including the activation of myeloid and lymphoid cells and induction of anti-tumor memory CD8 T cells in mice. In summary, systemically delivered LCB39 targeted tumor tissue and promoted robust anti-tumor activity with high tolerability in preclinical studies. LCB39 is a highly differentiated potent STING agonist with a safety profile, which suggested that LCB39 may have the potential to be the best-in-class STING agonist to treat solid cancers. LCB39 plans to enter first-in-human clinical study in early 2026. Citation Format: Jihye Oh, Hyun Joo Bae, Ye Seul Jang, Sung Min Kim, Ho Young Song, Sook Kyung Chang, Chul-Woong Chung. LCB39, a novel systemically deliverable STING agonist with strong preclinical activity and tolerability [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 4882.