Preclinical characterization of potent and selective oral PD-L1 small-molecule antagonists

Monoclonal antibodies against PD-L1 or PD-1 have been approved for the treatment of multiple tumor histologies by virtue of their ability to restore T cell effector function, increase T cell proliferation and enhance infiltration of tumor-reactive T cells. A small molecule approach to PD-(L)1 axis blockade may offer distinct benefits over the use of monoclonal antibodies including improved tissue penetration, titratability, absence of immunogenicity, ease of administration, and potential for fixed dose oral-oral therapeutic combinations. We have identified a novel class of small molecule PD-L1 antagonists that are capable of functional PD-(L)1 axis blockade by virtue of their ability to induce PD-L1 internalization. In vitro, select small molecules demonstrate high affinity to human PD-L1, potently disrupt the PD-L1:PD-1 interaction ( Citation Format: Liang-Chuan S. Wang, Holly Koblish, Yue Zhang, Ashwini Kulkarni, Maryanne Covington, Karen Gallagher, Gengjie Yang, Jonathan Rios-Doria, Christina Stevens, Michael Hansbury, Sybil O9Connor, Yan-ou Yang, Sharon Diamond, Krista Burke, Kaijiong Xiao, Jingwei Li, Wenqing Yao, Liangxing Wu, Peggy Scherle, Gregory Hollis, Reid Huber. Preclinical characterization of potent and selective oral PD-L1 small-molecule antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4480.