A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment
Jen‐Shin Song, Chih-Chun Chang, Chien-Huang Wu, Trinh Kieu Dinh, Jiing‐Jyh Jan, Kuan‐Wei Huang, Ming‐Chen Chou, Ting-Yun Shiue, Kai‐Chia Yeh, Yi‐Yu Ke, Teng‐Kuang Yeh, Yen‐Nhi Ngoc Ta, Chia‐Jui Lee, Jing‐Kai Huang, Yun‐Chieh Sung, Kak‐Shan Shia, Yunching Chen
Abstract
The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.