What question did this study set out to answer?

To develop a novel synthetic route for LSD1-targeting compounds and evaluate their inhibitory activity.

March 6, 20260 citations

A Novel Synthetic Route for Lysine-Specific Demethylase 1-Targeting Compounds: CC-90011 and MS9117.

JWJingying Wang YLYuying Li JZJingya Zhang

Key Points

To develop a novel synthetic route for LSD1-targeting compounds and evaluate their inhibitory activity.
Synthesis of LSD1-targeting compounds including CC-90011 and MS9117.
Utilization of the key intermediate LYY-23 for compound diversification.
Evaluation of compounds LYY-25 to LYY-29 for LSD1 inhibition.
CC-90011 demonstrated significant therapeutic potential for acute myeloid leukemia and solid tumors.
LYY-28 emerged as the most potent compound with an IC50 value of 3.59 nM.
All synthesized compounds showed varying degrees of LSD1 inhibitory activity.

Abstract

Lysine-specific demethylase 1 (LSD1) is a crucial target due to its essential role in cancers. CC-90011, the reversible and highly selective LSD1 inhibitor at the clinical stage, has demonstrated significant therapeutic potential in acute myeloid leukemia and solid tumors. Herein, we present a novel synthetic route to LSD1-targeting compounds that enables late-stage diversification; the key intermediate LYY-23 was used to synthesize CC-90011 and MS9117. In addition, compounds LYY-25 ∼ LYY-29 were synthesized and evaluated for LSD1 inhibition, all of which showed inhibitory activity, with LYY-28 emerging as the most potent compound (IC50 = 3.59 nM).

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