Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer.

Yong Wu, Jianbei Xi, Yue Li, Zheng Li, Yong Zhang, JianFei Wang, Guo-Huang Fan

Journal of medicinal chemistry 2023 Apr 13

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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 (Treg) 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 1, IPG7236) as the first small molecule to advance to the clinical stage. IPG7236 demonstrated an anti-cancer effect via modulating Treg 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 in vitro ADMET properties, pharmacokinetics, safety profiles, and in vivo efficacy.

Citation

Yong Wu, Jianbei Xi, Yue Li, Zheng Li, Yong Zhang, JianFei Wang, Guo-Huang Fan. Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer. Journal of medicinal chemistry. 2023 Apr 13;66(7):4548-4564