INCB 086550

INCB 086550 is an inhibitor of the protein-protein interaction between programmed cell death 1 (PD-1) and its ligand PD-L1.¹ It inhibits PD-1 binding to PD-L1 in CHO cells expressing human PD-L1 (EC₅₀ = 13.2 nM). INCB 086550 (1 µM) induces dimerization and internalization of PD-L1 in CHO cells expressing human PD-L1. It decreases the levels of unoccupied cell-surface PD-L1 in mouse MBT-2 bladder cancer cells expressing human PD-L1 at low, medium, or high levels (EC₅₀s = 3.7, 0.4, and 0.1 nM, respectively). It prevents PD-1-induced recruitment of Src homology region 2 domain-containing phosphatase (SHP) in a reporter assay using Jurkat T cells co-cultured with U2OS cells expressing human PD-L1 (IC₅₀ = 6.3 nM) and induces activation of nuclear factor of activated T cells (NFAT) in a reporter assay using Jurkat T cells co-cultured with CHO-K1 cells (IC₅₀ = 21.4 nM). In vivo, INCB 086550 (20 or 200 mg/kg per day) reduces tumor volume and intratumoral cell-surface levels of PD-L1, as well as increases CD8⁺ T cell tumor infiltration, in an MC-38 murine allograft model of colon carcinoma overexpressing human PD-L1 (MC-38-hPD-L1).

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1. Koblish, H.K., Wu, L., Wang, L.S., et al. Characterization of INCB086550: A potent and novel small-molecule PD-L1 inhibitor. Cancer Discov. 12(6), 1482-1499 (2022).