Abstract 5444: BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor

Abstract

Abstract PD-1/PD-L1 antibodies have entered mainstream of cancer treatment, but they came with limitations such as weak tumor penetration, immunogenicity, immune-related risks with a long half-life, and high cost. Small molecule inhibitors of PD-L1 are expected to overcome these limitations. We hereby present BPI-371153, an orally bioavailable small molecule that disrupts PD-1/PD-L1 interaction similar to PD-1/PD-L1 antibodies. BPI-371153 demonstrates high binding affinity to human PD-L1, induces PD-L1 dimeralization and disrupts PD-L1:PD-1 interaction (IC50 <1 nM by HTRF assay). BPI-371153 induces PD-L1 internalization with an IC50 value of 4.2 nM as detected by flow cytometry, activates nuclear factor of activated T cell (NFAT) signaling in cell-based reporter assay, and effectively stimulates IFN-γ release in human peripheral blood monocyte-mediated tumor cell killing assay. In a syngeneic mouse model with murine MC38 colon tumor cells expressing human PD-L1 (MC38-hPD-L1 model), BPI-371153 suppressed tumor growth to an extent comparable to an anti-PD-L1 antibody. In immunocompromised mice grafted with the same cell line, no growth inhibition was observed, confirming that the pharmacologic effect of BPI-371153 indeed came from the immune system. In addition, this compound exhibits favorable ADME properties, with high oral exposure across multiple pre-clinical species. Phase I clinical trial of BPI-371153 is planned for early 2022. Citation Format: Yiqian Wang, Xiangyan Jing, Hong Chen, Huijuan Zhang, Tianyi Ma, Yao Zhang, Chunhui Zhang, Guangzhi Zhang, Xiangyong Liu, Dan Yan, Jing Guo, Hong Lan, Jiabing Wang, Lieming Ding. BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor [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 5444.