Design, synthesis, and anti-AML activity of Hyt-based LSD1 degraders.

Abstract

Lysine-specific demethylase 1 (LSD1, KDM1A) drives oncogenic progression in acute myeloid leukemia (AML) through both catalytic histone demethylation and non-catalytic scaffolding interactions with oncogenic transcription factors. Conventional LSD1 inhibitors either suffer from severe off-target toxicity or fail to block LSD1's non-enzymatic oncogenic functions. In recent years, emerging targeted protein degradation technologies have enabled the elimination of target proteins, providing a promising alternative strategy for drug development. Herein, we report for the first time a panel of intracellular self-assembled LSD1 degraders rationally designed via hydrophobic tagging (Hyt) strategy. Upon covalent engagement with FAD cofactor within LSD1 active pocket, the parent precursor releases NEW-Hyts that continuously mediate LSD1 degradation. Systematic linkers and Hyt warheads investigation afforded compound 18 as the optimal candidate. Western blot verified that 18 induced LSD1 degradation up to 70.86% at 10 μM in MV4-11 AML cells, as a time- and dose-dependent manner. ELISA assay further confirmed the degradation activity of 18 against LSD1, with a degradation rate of 83.46% at 10 μM. Besides, CCK-8 proliferation assay demonstrated that 18 exerted potent anti-AML activity with an IC₅₀ value of 1.12 μM, far superior than parent LSD1 inhibitors (TCP and ORY-1001). Moreover, flow cytometry analysis further confirmed that 18 concentration-dependently induced AML cell apoptosis and arrested cell cycle progression at G0/G1 phase. Collectively, this work provides a novel low-molecular-weight (MW = 564.7), intracellular assembly LSD1 degrader, representing a promising strategy for targeted AML therapy.