Design, synthesis, and biological evaluation of ALK5 PROTAC degraders for pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) deposition, leading to irreversible scarring and respiratory failure. With limited treatment options, there is an urgent need for novel therapeutic strategies. Activin receptor-like kinase 5 (ALK5), a type I receptor serine/threonine kinase, serves as the principal mediator of transforming growth factor-β (TGF-β) signaling and a pivotal driver of PF pathogenesis. Given the central role of ALK5 in fibrogenesis, targeting ALK5 represents a promising therapeutic approach. Conventional ALK5 inhibitors primarily target kinase activity, whereas proteolysis-targeting chimeras (PROTACs) may offer a promising therapeutic strategy by inducing degradation of the target protein. Herein, we report the discovery of a series of novel ALK5-targeting PROTAC degraders. The lead compound, A31, induced ALK5 degradation in NIH3T3 cells and demonstrated inhibition of ALK5 downstream signaling and fibroblast activation. Furthermore, A31 exhibits favorable pharmacokinetics following intraperitoneal administration, in vivo anti-fibrotic efficacy, and no significant toxicity at efficacious doses. Collectively, our study supports the feasibility of ALK5-targeting degradation as a potential therapeutic strategy for pulmonary fibrosis and highlights the therapeutic potential of PROTAC-based strategies in fibrotic diseases.