Wu Yong, Xi Jianbei, Li Yue, Li Zheng, Zhang Yong, Wang JianFei, Fan Guo-Huang
J Med Chem. 2023 Apr 13;66(7):4548-4564. doi: 10.1021/acs.jmedchem.3c00030. Epub 2023 Mar 29.
Recently, there has been increasing evidence indicating that the CC chemokine receptor 8 (CCR8) plays an important role in mediating the recruitment and immunosuppressive function of regulatory T (T) cells in the tumor microenvironment. Therefore, the development of a specific CCR8 antagonist presents a potential therapeutic strategy against cancer. Despite a few small molecules having been reported as CCR8 antagonists, none has progressed to the clinical stage. Herein, we described a potent and selective CCR8 antagonist (compound , IPG7236) as the first small molecule to advance to the clinical stage. IPG7236 demonstrated an anti-cancer effect via modulating T and cytotoxic T (CD8 T) cells. IPG7236 alone or in combination with PD-1 antibody exhibited significant tumor suppression effects in the mouse xenograft model of human breast cancer. IPG7236 is a promising clinical candidate that targets CCR8 with excellent ADMET properties, pharmacokinetics, safety profiles, and efficacy.
最近，越来越多的证据表明，CC趋化因子受体8（CCR8）在介导肿瘤微环境中调节性T（Treg）细胞的募集和免疫抑制功能方面发挥着重要作用。因此，开发一种特异性CCR8拮抗剂是一种潜在的抗癌治疗策略。尽管已有一些小分子被报道为CCR8拮抗剂，但尚无一种进入临床阶段。在此，我们描述了一种强效且选择性的CCR8拮抗剂（化合物IPG7236），它是首个进入临床阶段的小分子药物。IPG7236通过调节Treg和细胞毒性T（CD8+ T）细胞发挥抗癌作用。IPG7236单独使用或与PD-1抗体联合使用，在人乳腺癌小鼠异种移植模型中均表现出显著的肿瘤抑制作用。IPG7236是一个有前景的临床候选药物，它靶向CCR8，具有优异的药物代谢动力学、安全性和疗效特征（ADMET特性）。
