Non-carbohydrate Galectin-1 inhibitors as promising anticancer agents: Design strategies, structure activity relationship and mechanistic insights

Galectin-1 (gal-1) emerges as a potential biomarker for cancer diagnosis, prognosis, and therapy. Gal-1 plays a pivotal role in multiple stages of tumor progression, encompassing tumor transformation, tumor cell adhesion and migration, angiogenesis, and evasion of immune responses. Despite efforts to develop carbohydrate-based gal-1 inhibitors targeting the carbohydrate recognition domain, challenges still persist such as limited selectivity due to high water solubility, poor pharmacokinetics, and expensive synthetic routes that limit their effectiveness against overexpressed gal-1 in cancer cells. Therefore, next generation anticancer agents targeting gal-1 with improved pharmacokinetics and target selectivity may overcome current challenges. Various synthetic strategies have been explored, including substituting the carbohydrate nucleus with bioactive heterocycles in small molecules, employing sugar mimetics, or investigating alternative allosteric inhibition with peptides and peptidomimetics. This review describes gal-1 multifaceted roles in tumor biology, rationalized approaches, design strategies for non-carbohydrate gal-1 inhibitors, and provides insights into structure-activity relationship and gal-1 inhibitory mechanisms.