Discovery of a Selective, Novel TGF-βR1 Inhibitor GFH018 for the Treatment of Solid Tumors

Transforming growth factor-β (TGF-β) signaling pathway plays an important role in tumorigenesis. Inhibition of the TGF-β type I receptor kinase is considered an attractive strategy for the treatment of tumor growth and metastasis. This paper describes the discovery of GFH018, a highly potent and selective ATP-competitive inhibitor of TGF-βR1 that entered phase II clinical trials. The scaffold-hopping strategy was leveraged to successfully obtain a novel core of TGF-βR1 inhibitors. GFH018 exhibited high selectivity against p38α and good target inhibitory activity. Additionally, GFH018 displayed favorable in vitro ADME and pharmacokinetic profiles across species. In murine tumor mouse models, either the monotherapy of GFH018 or the combination with an anti-PD-L1 antibody suppressed tumor growth, and potent inhibition of cancer cell migration in vivo was observed. Mechanistic studies revealed that GFH018 not only reactivated the immune system by blocking Treg- and M2 macrophage-mediated immunosuppression but also inhibited tumor vascular angiogenesis.