Abstract 5599: A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1

Abstract

Abstract Introduction: High Mobility Group Box1 (HMGB1) is a kind of DAMP to modulate immune responses in various conditions, including the tumor microenvironment. In various cancers, it has been reported that cytoplasmic localization of HMGB1 is correlated with poor prognosis. Here, we present a novel small-molecule drug candidate, SB17170, which inhibits immune-suppressive cells in tumor microenvironments by specific binding to HMGB1. Methods: SB17170 is a pro-drug of active metabolite SB1703 which was identified in cell-based phenotypic screening. SB1703 modulates immune responses by inhibiting the secretion of various cytokines from activated macrophages. HMGB1 was revealed as the target protein of SB1703 using Fluorescence difference In Two-dimensional Gel-Electrophoresis (FITGE). The antitumor activity of SB1703 was analyzed in B16F10 murine syngeneic model. Results: SB17170 is orally available drug candidate at the clinical development stage for solid tumors. The active metabolite SB1703, bound to HMGB1, was observed in activated MDSC, but not in immature MDSC, and inhibited the activity and cytokine release of MDSC at the submicromolar range. The antitumor activity of SB17170 was observed in B16F10 murine syngeneic model, but not in immunodeficient NOG model, suggesting that SB17170 requires the adaptive immune system for its antitumor activity. The oral treatment of SB17170 in tumor-bearing mice induced intratumor T cell infiltration, but reduced the number of MDSC from day 3. SB17170 also repressed HMGB1 levels as well as MDSC in the blood. In combination with immune checkpoint inhibitors against PD1, PD-L1, and CTLA4, SB17170 enhanced the antitumor responses. Conclusions: We presented here orally available small-molecule drug candidate, SB17170, which selectively binds to HMGB1 and represses MDSC in tumor microenvironment. SB17170 showed the antitumor activity in B16F10 murine syngeneic models, but not in immunodeficient background, suggesting that its mechanism of action is based on antitumor immune responses. Citation Format: Young Il Choi, Sungoh Ahn, Hyo Young Kim, Na Jin Jung, Jae Jin Lee, Seung Bum Park. A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5599.