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 (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.