Discovery of 7-Aminofuro[2,3- c ]pyridine-Based Irreversible Inhibitors of TGFβ-Activated Kinase 1 (TAK1) with In Vivo Antitumor Activity

Abstract TGFβ-activated kinase 1 (TAK1) plays essential roles in proinflammatory and prosurvival signaling pathways, and has been implicated in various human diseases, including cancer and inflammation. Although several TAK1 inhibitors have been reported, an effective tool compound with a combination of favorable potency, selectivity, and in vivo efficacy is still lacking. Herein, we present a 7-aminofuro[2,3-c]pyridine-based α,β-unsaturated aldehyde (compound 26) as a potent TAK1 irreversible covalent inhibitor. This compound exhibited excellent inhibitory activity for TAK1-dependent signaling in cells and demonstrated a sustained TAK1 inhibition effect in vivo. Furthermore, it significantly prevented tumor growth in a lymphoma (DoHH2) xenograft mouse model. Although a contribution from the inhibition of other kinases to the observed effects cannot be ruled out, compound 26 provides a promising starting point for further optimization of TAK1 selectivity and pharmacokinetic properties toward the development of TAK1-targeted agents.