Development of a potent benzonitrile-based inhibitor of glutaminyl-peptide cyclotransferase-like protein (QPCTL) with antitumor efficacy
Lei Yu, Pengcheng Zhao, Yaoliang Sun, Zening Zheng, Wenhao Du, Lishan Zhang, Yaxu Li, Long-Yan Xie, Shilin Xu, Ping Wang
Abstract
Immune checkpoint therapies manipulating the immune system to eliminate tumor cells have shown remarkable clinical efficacy in treating various cancers. CD47, an emerging efficient immune checkpoint, is crucial for cancer cells to evade macrophage-mediated phagocytosis by interaction with signal-regulatory protein α (SIRPα). Antibodies blocking the CD47/SIRPα interaction have been effective to promote macrophage-mediated phagocytosis in various types of cancer in mice and humans. CD47 is not only highly expressed in tumor cells, but also normal cells, such as red blood cells (RBCs). Thus, during clinical trials involving cancer patients, anti-CD47 antibodies may promote the macrophages-mediated phagocytosis of RBCs, ultimately inducing undesirable anemia side effects. In contrast, small molecule inhibitors interrupting CD47/SIRPα axis have shown potential to overcome the anemia, possibly due to their lower immunogenicity and shorter half-life compared to antibodies. 1 Hence, developing the novel strategies, especially those without the anemia side effect, to intervene in CD47/SIRPα interaction will benefit cancer immunotherapy.