%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 Bin Yu
%A Bing Zhao
%A Dandan Shen
%A Fengzhi Suo
%A Hongmin Liu
%A Junwei Wang
%A Lina Ding
%A Liying Ma
%A Pengfei Geng
%A Taoqian Zhao
%A Xudong Sun
%A Yichao Zheng
%A Zhizheng Wang
%A Zhonghua Li
%A Zhongrui Li
%J Archive of "Acta Pharmaceutica Sinica. B".
%D 2019
%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£¿¦Ìmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49£¿nmol/L, and Ki = 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£¿¦Ìmol/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
%K AML
%K acute myeloid leukemia
%K ATRA
%K all-trans retinoic acid
%K BTK
%K Bruton£¿s tyrosine kinase
%K CDK
%K cyclin-dependent kinase
%K CuAAC
%K copper-catalyzed azide-alkyne cycloadditions
%K DABCO
%K triethylenediamine
%K DCM
%K dichloromethane
%K DNMTs
%K DNA methyltransferases
%K DIPEA
%K N
%K N-diisopropylethylamine
%K EA
%K ethyl acetate
%K EtOH
%K ethanol
%K GSCs
%K glioma stem cells
%K FAD
%K flavin adenine dinucleotide
%K LSD1
%K histone lysine specific demethylase 1
%K MAO
%K monoamine oxidase
%K MeOH
%K methanol
%K PAINS
%K pan-assay interference compound
%K Rt
%K room temperature
%K SAR
%K structure¡ªactivity relationship
%K TCP
%K tranylcypromine
%K TEA
%K triethylamine
%K THF
%K terahydrofuran
%K TLC
%K thin layer chromatography. Epigenetic regulation
%K Histone demethylase
%K LSD1
%K Pyrimidine-triazole
%K Mercapto heterocycles
%K Antiproliferative ability
%K AML treatment
%K Structure¨Cactivity relationships (SARs)
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663923/