Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors.

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC 50 of 1.230 μM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment. Image 1 • Compound 9e was designed and synthesized based on a lead compound obtained from our in-house compound library. • Compound 9e inhibits LSD1 (IC50 = 1.230 μM) and shows good anti-proliferation activity in THP-1 cells. • Compound 9e can significantly increase the expression of CD86 and induce differentiation of THP-1 cells. • Compound 9e is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. [ABSTRACT FROM AUTHOR]