Abstract LB-A17: Discovery and characterization of a novel small molecule antagonist of PD-L1

Abstract

Abstract Introduction: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for various cancers. Unlike antibodies, small molecule inhibitors may offer potential advantages in oral dosing, adjustable control of drug exposure, improved accessibility to tumor and many other aspects. Therefore, small molecule antagonist which can efficiently block interaction of PD-1 and PD-L1 may render a novel alternative treatment approach with potentially improved clinical benefits. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel and orally available small molecule PD-L1 antagonist ABSK-041, demonstrating robust T-cell activating ability and strong anti-tumor activity in various preclinical models. Method: ABSK-041’s ability to block PD-1-PD-L1 interaction was evaluated by HTRF assay and cellular luciferase reporter assay. Its biological activity was evaluated in vitro in MLR and in vivo in syngeneic tumor models. Results: ABSK-041 strongly inhibits PD-1-PD-L1 interaction with IC50<1 nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. It also efficiently rescues cytokine production of PD-L1 suppressed CD8+ T cell to a level comparable with PD-L1 antibody. In in vivo studies, oral administration of ABSK-041 strongly inhibits tumor growth to a extent similar to therapeutic anti-PD-L1 antibody. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK-041. Conclusion: ABSK-041, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist. Its superior profile supports fast-track preclinical development. Citation Format: Haiyan Ying, Fei Yang, Mingming Zhang, Yongxian Zhang, Yuan Zhao, Xin Chen, Lei Zhang, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a novel small molecule antagonist of PD-L1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A17. doi:10.1158/1535-7163.TARG-19-LB-A17