Blocking the PD-(L)1 immune checkpoint axis with therapeutic antibodies has proven to be an effective treatment modality for multiple cancer histologies. Orally bioavailable small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies.

This presentation will detail our discovery evolution that led to the discovery of a first-in-class small molecule PDL1 inhibitor INCB89550 which is currently in clinical trials for the treatment of cancer. The presentation will also detail our characterization of novel small molecule antagonists of the PD-(L)1 axis that function by inducing dimerization and subsequent internalization of the PD-L1 protein, effectively depleting the ligand from the cell membrane and preventing PD-1 activation on T cells.

Citation Format: Liangxing Wu. Discovery of INCB86550: A potent, orally bioavailable small molecule inhibitor of PDL1 for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND01.