LSD1-based dual-target inhibitors as emerging anticancer agents: pharmacological perspectives and SAR exploration

LSD1 is a key epigenetic eraser that demethylates the histone proteins and regulates transcription. Overexpression of LSD1 drives the development of multiple cancers, such as prostate, breast, gastric, lung, colorectal cancers, and acute myeloid leukemia. Although several LSD1 inhibitors have shown promise for cancer therapy, monotherapy faces challenges such as low selectivity, high toxicity, and drug resistance. To overcome these drawbacks and achieve synergistic anticancer effects, researchers have focused on dual inhibitors that target LSD1 along with other oncogenic partners, including HDAC, EGFR, EZH2, tubulin, ERα, G9a, JmjC, DCN1, and SMOX. This review aims to provide recent design strategies and SAR for LSD1-based dual inhibitors, emphasizing the fusion of different LSD1 pharmacophore (tranylcypromine, pargyline, pyridine, 5-cyano-3-phenylindole, indole, benzyl/aryl piperazine, triazole-dithiocarbamate and substituted triazole scaffold) with various heterocyclic and zinc-binding cores such as hydroxamic acids, bipyridine, hydroxy quinoline to generate hybrids capable of inducing apoptosis, blocking cell-cycle, differentiation. This review explores the pharmacological role of LSD1 in oncogenesis and offers structural and SAR insights to guide the design of LSD1-based dual inhibitors.