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. Its pivotal involvement spans various stages of tumor progression, including tumor transformation, tumor cell adhesion and migration, angiogenesis, and immune escape. Although carbohydrate-based gal-1 inhibitors have been developed to selectively target its carbohydrate recognition domain, the main drawbacks include limited target selectivity due to high water solubility, poor pharmacokinetics, low therapeutic indices, and expensive synthetic routes that lowers their utility to target overexpressed gal-1 in cancer cells. Hence, there is a pressing need for enhanced gal-1-targeting anticancer agents with improved pharmacokinetics and target selectivity. 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 relationships and mechanisms.