A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment.
Jen-Shin SongChih-Chun ChangChien-Huang WuTrinh Kieu DinhJiing-Jyh JanKuan-Wei HuangMing-Chen ChouTing-Yun ShiueKai-Chia YehYi-Yu KeTeng-Kuang YehYen-Nhi Ngoc TaChia-Jui LeeJing-Kai HuangYun-Chieh SungKak-Shan ShiaYunching ChenPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.