ALK5 kinase inhibitors in drug discovery: Structural insights and therapeutic applications.

Activin receptor-like kinase-5 (ALK5), a pivotal component of the transforming growth factor-β (TGF-β) signaling pathway, plays a critical role in tumorigenesis, inflammation, and fibrosis. The development of selective ALK5 inhibitors with antitumor and antifibrotic properties has emerged as a promising strategy in cancer therapeutics. This review systematically summarizes recent advances in ALK5 inhibitor research, focusing on clinical candidates, synthetic and natural compounds, and their structure-activity relationships (SARs). Key pharmacological aspects, including pharmacokinetic (PK) and pharmacodynamic (PD) profiles, are discussed to provide insights into rational drug design. Furthermore, we highlight challenges in clinical translation, such as cardiotoxicity, and propose future directions for optimizing ALK5-targted therapies.