Tranylcypromine-derived LSD1 inhibitors: Synthetic strategies, structure-activity relationships, and anticancer potential.

Lysine-specific demethylase 1 (LSD1), frequently overexpressed in cancers, drives tumor progression by demethylating oncogenic histone marks H3K4me1/2 and H3K9me1/2, establishing it as a compelling therapeutic target. Inhibition of LSD1 suppresses cancer cell proliferation, invasion, and migration, prompting extensive development of inhibitors since its discovery. Tranylcypromine derivatives represent the most potent inhibitor class, exhibiting sub-micromolar to nanomolar IC values. Clinically evaluated candidates like TCP, ORY-1001, and INCB059872; administered alone or in combination; irreversibly inhibit LSD1 by binding its FAD cofactor. This review systematically analyzes all reported tranylcypromine-based LSD1 inhibitors, elucidating their structure-activity relationships (SAR), synthetic strategies, mechanistic insights, and anticancer profiles. Key SAR modifications enhancing potency and selectivity are highlighted. Collectively, these inhibitors demonstrate significant therapeutic promise. We further discuss challenges (e.g., selectivity, resistance), opportunities, and future directions for optimizing LSD1-targeted cancer therapies.