Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. Several LSD1 inhibitors have advanced into clinical trials. Following our last annual review on LSD1 inhibitors in 2020 (Eur. J. Med. Chem. 2021, 214, 113254), in this review we aim to update LSD1 inhibitors including natural products, synthetic compounds and cyclic peptides reported during 2021. Design strategies, structure-activity relationships, binding model analysis and modes of action are highlighted. In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent [F]30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors.