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

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_reg) 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 T_reg 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.