Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents

The multifunctional cytokine TGF beta plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGF beta signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGF beta receptor kinase inhibitors with excellent selectivity for TGF beta receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.