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

• Published in: Acta pharmaceutica Sinica. B 2019-07, Vol.9 (4), p.794-808
• Main Authors: Li, Zhonghua, Ding, Lina, Li, Zhongrui, Wang, Zhizheng, Suo, Fengzhi, Shen, Dandan, Zhao, Taoqian, Sun, Xudong, Wang, Junwei, Liu, Ying, Ma, Liying, Zhao, Bing, Geng, Pengfei, Yu, Bin, Zheng, Yichao, Liu, Hongmin
• Format: Article
• Language: English
• Subjects: Original article
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2019.01.001

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 (IC = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound (IC = 49 nmol/L, and = 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 . Compound 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 IC values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, significantly inhibited colony formation and caused remarkable morphological changes. Compound 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.