Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).
- Author:
Zhonghua LI
1
;
Lina DING
1
;
Zhongrui LI
1
;
Zhizheng WANG
1
;
Fengzhi SUO
1
;
Dandan SHEN
1
;
Taoqian ZHAO
1
;
Xudong SUN
1
;
Junwei WANG
1
;
Ying LIU
1
;
Liying MA
1
;
Bing ZHAO
1
;
Pengfei GENG
1
;
Bin YU
1
;
Yichao ZHENG
1
;
Hongmin LIU
1
Author Information
- Publication Type:Journal Article
- Keywords: AML treatment; AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; Antiproliferative ability; BTK, Bruton׳s tyrosine kinase; CDK, cyclin-dependent kinase; CuAAC, copper-catalyzed azide-alkyne cycloadditions; DABCO, triethylenediamine; DCM, dichloromethane; DIPEA, N,N-diisopropylethylamine; DNMTs, DNA methyltransferases; EA, ethyl acetate; Epigenetic regulation; EtOH, ethanol; FAD, flavin adenine dinucleotide; GSCs, glioma stem cells; Histone demethylase; LSD1; LSD1, histone lysine specific demethylase 1; MAO, monoamine oxidase; MeOH, methanol; Mercapto heterocycles; PAINS, pan-assay interference compound; Pyrimidine-triazole; Rt, room temperature; SAR, structure—activity relationship; Structure–activity relationships (SARs); TCP, tranylcypromine; TEA, triethylamine; THF, terahydrofuran; TLC, thin layer chromatography.
- From: Acta Pharmaceutica Sinica B 2019;9(4):794-808
- CountryChina
- Language:English
- 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 (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.
