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Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).


ABSTRACT: 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??mol/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??mol/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.

SUBMITTER: Li Z 

PROVIDER: S-EPMC6663923 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).

Li Zhonghua Z   Ding Lina L   Li Zhongrui Z   Wang Zhizheng Z   Suo Fengzhi F   Shen Dandan D   Zhao Taoqian T   Sun Xudong X   Wang Junwei J   Liu Ying Y   Ma Liying L   Zhao Bing B   Geng Pengfei P   Yu Bin B   Zheng Yichao Y   Liu Hongmin H  

Acta pharmaceutica Sinica. B 20190105 4


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 <b>8a</b> (IC<sub>50</sub> = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound <b>15u</b> (IC<sub>50</sub> = 49 nmol/L, and <i>K</i> <sub>i</sub> = 16 nmol/L), which inhibited LSD1 reversi  ...[more]

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