ALDH1A inhibitors: Research advances in cancer therapeutics

Aldehyde dehydrogenase 1A (ALDH1A), a cytosolic enzyme, plays a critical role in tumorigenesis, cancer progression, and therapy resistance by maintaining cancer stem cell properties across various malignancies. Dysregulation of ALDH1A is implicated in the progression of numerous human diseases, including various cancers, metabolic disorders, and neurodegenerative conditions. Consequently, ALDH1A represents a promising therapeutic target, which underscores the urgent need to develop small-molecule inhibitors targeting ALDH1A. In recent years, research groups have developed a series of highly selective and potent ALDH1A inhibitors (e.g., coumarin-based compounds, disulfiram derivatives). These inhibitors have demonstrated significant antitumor efficacy, low cytotoxicity, and favorable pharmacokinetic profiles, which highlights their broad clinical potential. This review summarizes the applications and recent advances of the ALDH1A family in the treatment of various cancers, with a particular focus on the structural optimization and structure-activity relationships (SAR) of small-molecule inhibitors, their mechanisms of action and future development directions. This work is significant for facilitating the clinical translation of novel small-molecule inhibitors and for improving strategies to overcome drug resistance.