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

Zhonghua Li; Lina Ding; Zhongrui Li; Zhizheng Wang; Fengzhi Suo; Dandan Shen; Taoqian Zhao; Xudong Sun; Junwei Wang; Ying Liu; Liying Ma; Bing Zhao; Pengfei Geng; Bin Yu; Yichao Zheng; Hongmin Liu

doi:10.1016/j.apsb.2019.01.001

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

Acta Pharm Sin B. 2019 Jul;9(4):794-808. doi: 10.1016/j.apsb.2019.01.001. Epub 2019 Jan 5.

Authors

Zhonghua Li^{1

2

3}, Lina Ding^{1

2

3}, Zhongrui Li^{1

2

3}, Zhizheng Wang^{1

2

3}, Fengzhi Suo^{1

2

3}, Dandan Shen^{1

2

3}, Taoqian Zhao^{1

2

3}, Xudong Sun^{1

2

3}, Junwei Wang^{1

2

3}, Ying Liu^{1

2

3}, Liying Ma^{1

2

3}, Bing Zhao^{1

2

3}, Pengfei Geng^{1

2

3}, Bin Yu^{1

4

2

3}, Yichao Zheng^{1

2

3}, Hongmin Liu^{1

2

3}

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
² Co-Innovation Center of Henan Province for New Drug R&D and Preclinical Safety, Zhengzhou 450001, China.
³ Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.

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 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.

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..