%0 Journal Article
%T Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).
%A Li Z
%A Ding L
%A Li Z
%A Wang Z
%A Suo F
%A Shen D
%A Zhao T
%A Sun X
%A Wang J
%A Liu Y
%A Ma L
%A Zhao B
%A Geng P
%A Yu B
%A Zheng Y
%A Liu H
%J Acta Pharm Sin B
%V 9
%N 4
%D Jul 2019
%M 31384539
%F 14.903
%R 10.1016/j.apsb.2019.01.001
%X Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and K i = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.