Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy

• Published in: Neoplasia (New York, N.Y.) Vol. 23; no. 3; pp. 281 - 293
• Main Authors: Wang, Fengling, Ye, Wenling, Wang, Shuang, He, Yongxing, Zhong, Haiyang, Wang, Yuwei, Zhu, Yongchang, Han, Jianting, Bing, Zhitong, Ji, Shaoping, Liu, Huanxiang, Yao, Xiaojun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2021; Neoplasia Press; Elsevier
• Subjects: APBC; Cancer immunotherapy; Inhibitor; Original article; PD-1; PD-L1; HTRF; ALP; IHC; BMS; GPT; FACS; Cancer immunotherapy; GOT; APBC; DEGs; RNA-seq; SPR; ALB; mAbs; PD-L1; Inhibitor; TILs; PD-1; SP
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2021.01.001

Blockade of the PD-1/PD-L1 immunologic checkpoint using monoclonal antibodies has provided breakthrough therapies against cancer in the recent years. Nevertheless, intrinsic disadvantages of therapeutic antibodies may limit their applications. Thus, blocking of the PD-1/PD-L1 interaction by small molecules may be a promising alternative for cancer immunotherapy. We used a docking-based virtual screening strategy to rapidly identify new small molecular inhibitors targeting PD-L1. We demonstrated that a small molecule compound (N-[2-(aminocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide [APBC]) could effectively interrupt the PD-1/PD-L1 interaction by directly binding to PD-L1, presenting the KD and IC50 values at low-micromolar level. Molecular docking study revealed that APBC may have function through a PD-L1 dimer-locking mechanism, occluding the PD-1 interaction surface of PD-L1. We further confirmed the ligand blocking activity and T cell-reinvigoration potency of APBC using cell-based assays. APBC could dose-dependently elevate cytokine secretions of the primary T-lymphocytes that are cocultured with cancer cells. Importantly, APBC displayed superior antitumor efficacy in hPD-L1 knock-in B16F10-bearing mouse model without the induction of observable liver toxicity. Analyses on the APBC-treated mice further revealed drastically elevated levels of infiltrating CD4+ and CD8+ T cells, and inflammatory cytokines production in tumor microenvironment. The APBC compound could serve as a privileged scaffold in the design of improved PD pathway modulators, thus providing us promising drug candidates for tumor immunotherapy.