Citation: Wang Shuai, Shen Dandan, Zhao Lijie, Yuan Xiaohan, Cheng Jialing, Yu Bin, Zheng Yichao, Liu Hongmin. Discovery of [1, 2, 4]triazolo[1, 5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors[J]. Chinese Chemical Letters, ;2020, 31(2): 418-422. doi: 10.1016/j.cclet.2019.08.029 shu

Discovery of [1, 2, 4]triazolo[1, 5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors

Key Laboratory of Technology of Drug Preparation, Ministry of Education of China & School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

yubin@zzu.edu.cn

yichaozheng@zzu.edu.cn

liuhm@zzu.edu.cn

Received Date: 26 June 2019
Revised Date: 14 August 2019
Accepted Date: 16 August 2019
Available Online: 17 August 2019

Figures(4)

Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1, 2, 4]triazolo[1, 5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC₅₀ values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC₅₀ value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1, 2, 4]triazolo[1, 5-a] pyrimidine is a new template for the development of new BRD4 inhibitors.
- Epigenetic regulation,
- BRD4 inhibitor,
- [1, 2, 4]triazolo[1, 5-a]pyrimidine,
- THP-1 cells,
- AML treatment
1. [1]
  P. Filippakopoulos, J. Qi, S. Picaud, et al., Nature 468(2010) 1067-1073. doi: 10.1038/nature09504
2. [2]
  E. Nicodeme, K.L. Jeffrey, U. Schaefer, et al., Nature 468(2010) 1119-1123. doi: 10.1038/nature09589
3. [3]
  P. Filippakopoulos, S. Knapp, Nat. Rev. Drug Discov. 13(2014) 337-356. doi: 10.1038/nrd4286
4. [4]
  J. Shi, C.R. Vakoc, Mol. Cell 54(2014) 728-736.
5. [5]
  A. Wyce, Y. Degenhardt, Y. Bai, et al., Oncotarget 4(2013) 2419-2429.
6. [6]
  V. Sahai, K. Kumar, L.M. Knab, et al., Mol. Cancer Ther. 13(2014) 1907-1917. doi: 10.1158/1535-7163.MCT-13-0925
7. [7]
  C. Pastori, M. Daniel, C. Penas, et al., Epigenetics 9(2014) 611-620. doi: 10.4161/epi.27906
8. [8]
  D. Da Costa, A. Agathanggelou, T. Perry, et al., Blood Cancer J. 3(2013) e126. doi: 10.1038/bcj.2013.24
9. [9]
  Z. Cheng, Y. Gong, Y. Ma, et al., Clin. Cancer Res. 19(2013) 1748-1759. doi: 10.1158/1078-0432.CCR-12-3066
10. [10]
  M. Pervaiz, P. Mishra, S. Gunther, Chem. Rec. 18(2018) 1808-1817. doi: 10.1002/tcr.201800074
11. [11]
  Y. Duan, Y. Guan, W. Qin, et al., MedChemComm 9(2018) 1779-1802. doi: 10.1039/C8MD00198G
12. [12]
  Z. Liu, B. Tian, H. Chen, et al., Eur. J. Med. Chem. 151(2018) 450-461. doi: 10.1016/j.ejmech.2018.04.006
13. [13]
  M. Pérez-Salvia, M. Esteller, Epigenetics 12(2016) 323-339. doi: 10.1080/15592294.2016.1265710
14. [14]
  J. Lu, Y. Qian, K. Raina, et al., Blood 126(2015) 755-763. doi: 10.1182/blood.V126.23.755.755
15. [15]
  G.M. Matthews, S. Gandolfi, J. Bruggentheis, et al., Blood 128(2016) 1062. doi: 10.1182/blood.V128.22.1062.1062
16. [16]
  G.E. Winter, D.L. Buckley, J. Paulk, et al., Science 348(2015) 1376-1381. doi: 10.1126/science.aab1433
17. [17]
  S. Crunkhorn, Nat. Rev. Drug Discov. 14(2015) 459. doi: 10.1038/nrd4670
18. [18]
  L. Ouyang, L. Zhang, J. Liu, et al., J. Med. Chem. 60(2017) 9990-10012. doi: 10.1021/acs.jmedchem.7b00275
19. [19]
  Z. Liu, P. Wang, H. Chen, et al., J. Med. Chem. 60(2017) 4533-4558. doi: 10.1021/acs.jmedchem.6b01761
20. [20]
  G. Andrieu, A.C. Belkina, G.V. Denis, Drug Discov. Today 19(2016) 45-50. doi: 10.1016/j.ddtec.2016.06.004
21. [21]
  R. Vazquez, M.E. Riveiro, L. Astorgues-Xerri, et al., Oncotarget 8(2017) 7598-7613. doi: 10.18632/oncotarget.13814
22. [22]
  L. Chang, M. Xiao, L. Yang, et al., Bioorg. Med. Chem. 26(2018) 5006-5017. doi: 10.1016/j.bmc.2018.08.021
23. [23]
  Z.H. Li, X.Q. Liu, T.Q. Zhao, et al., Eur. J. Med. Chem. 139(2017) 741-749. doi: 10.1016/j.ejmech.2017.08.042
24. [24]
  Z.H. Li, X.Q. Liu, T.Q. Zhao, et al., Bioorg. Med. Chem. Lett. 27(2017) 4377-4382. doi: 10.1016/j.bmcl.2017.08.021
25. [25]
  Z.H. Li, X.Q. Liu, P.F. Geng, et al., Eur. J. Med. Chem. 138(2017) 1034-1041. doi: 10.1021/acsmedchemlett.6b00423
26. [26]
  Z.H. Li, X.Q. Liu, P.F. Geng, et al., ACS Med. Chem. Lett. 8(2017) 384-389. doi: 10.1021/acsmedchemlett.6b00423
27. [27]
  B. Wang, B. Zhao, L.P. Pang, et al., Pharmacol. Res. 122(2017) 66-77. doi: 10.1016/j.phrs.2017.05.025
28. [28]
  B. Yu, X.J. Shi, Y.F. Zheng, et al., Eur. J. Med. Chem. 69(2013) 323-330. doi: 10.1016/j.ejmech.2013.08.029
29. [29]
  L.H. Huang, Y.F. Zheng, Y.Z. Lu, et al., Steroids 77(2012) 710-715. doi: 10.1016/j.steroids.2012.03.002
30. [30]
  S. Yuan, B. Yu, H.M. Liu, Adv. Synth. Catal. 361(2019) 59-66. doi: 10.1002/adsc.201801226
31. [31]
  S. Wang, L. Zhao, X.J. Shi, et al., J. Med. Chem. 62(2019) 2772-2797. doi: 10.1021/acs.jmedchem.9b00113
32. [32]
  Z. Li, L. Ding, Z. Li, et al., Acta Pharm. Sin. B 9(2019) 794-808.
33. [33]
  S. Yuan, S. Wang, M. Zhao, et al., Chin. Chem. Lett. (2019), doi: http://dx.doi.org/10.1016/j.cclet.2019.07.019.
34. [34]
  K. Huynh, C.L. Partch, Curr. Protoc. Protein Sci. 79(2015) 28.9.1-28.9.14.
35. [35]
  J. Zuber, J. Shi, E. Wang, et al., Blood 120(2012) 2843-2852.
36. [36]
  J. Zuber, J. Shi, E. Wang, et al., Nature 478(2011) 524-528. doi: 10.1101/gad.17269211
37. [37]
  J.E. Delmore, G.C. Issa, M.E. Lemieux, et al., Cell 146(2011) 904-917. doi: 10.1016/j.cell.2011.08.017
38. [38]
  J.A. Mertz, A.R. Conery, B.M. Bryant, et al., Proc. Natl. Acad. Sci. U. S. A. 108(2011) 16669-16674. doi: 10.1073/pnas.1108190108
39. [39]
  Y.J. Jeong, H.S. Hoe, J. Cell. Biochem. 119(2018) 2036-2047. doi: 10.1002/jcb.26366
40. [40]
  W.S. El-Deiry, Cancer Res. 76(2016) 5189-5191. doi: 10.1158/0008-5472.CAN-16-2055
41. [41]
  A.L. Gartel, Mol. Cancer Ther. 5(2006) 1385-1386. doi: 10.1158/1535-7163.MCT-06-0163
42. [42]
  J.H. Jeong, S.S. Kang, K.K. Park, et al., Mol. Cancer Ther. 9(2010) 2102-2113. doi: 10.1158/1535-7163.MCT-09-1159
43. [43]
  D.M. Lepley, J.C. Pelling, Mol. Carcinog. 19(1988) 74-82. doi: 10.1002/(sici)1098-2744(199707)19:2<74::aid-mc2>3.0.co;2-l
44. [44]
  T. Gulappa, R.S. Reddy, S. Suman, A.M. Nyakeriga, C. Damodaran, Cancer Lett. 337(2013) 177-183. doi: 10.1016/j.canlet.2013.05.014
45. [45]
  A. Cieslar-Pobuda, V. Knoflach, M.V. Ringh, et al., Biochim. Biophys. Acta-Mol. Cell Res. 1864(2017) 1359-1369. doi: 10.1016/j.bbamcr.2017.04.017
46. [46]
  P. Filippakopoulos, J. Qi, S. Picaud, et al., Nature 468(2010) 1067-1073. doi: 10.1038/nature09504
47. [47]
  F.Vollmuth, W. Blankenfeldt, M.Geyer, J. Biol.Chem. 284(2009)36547-36556. doi: 10.1074/jbc.M109.033712
48. [48]
  P.F. vonVoigtlander, R.N. Straw, Drug Develop. Res. 6(1985) 1-12. doi: 10.1002/ddr.430060102
1. [1]
  Bairu Meng , Zongji Zhuo , Han Yu , Sining Tao , Zixuan Chen , Erik De Clercq , Christophe Pannecouque , Dongwei Kang , Peng Zhan , Xinyong Liu . Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs. Chinese Chemical Letters, 2024, 35(6): 108827-. doi: 10.1016/j.cclet.2023.108827
2. [2]
  Chunhua Ma , Mengjiao Liu , Siyu Ouyang , Zhenwei Cui , Jingjing Bi , Yuqin Jiang , Zhiguo Zhang . Metal-free construction of diverse 1,2,4-triazolo[1,5-a]pyridines on water. Chinese Chemical Letters, 2025, 36(1): 109755-. doi: 10.1016/j.cclet.2024.109755
3. [3]
  Jiao Chen , Zihan Zhang , Guojin Sun , Yudi Cheng , Aihua Wu , Zefan Wang , Wenwen Jiang , Fulin Chen , Xiuying Xie , Jianli Li . Benzo[4,5]imidazo[1,2-a]pyrimidine-based structure-inherent targeting fluorescent sensor for imaging lysosomal viscosity and diagnosis of lysosomal storage disorders. Chinese Chemical Letters, 2024, 35(11): 110050-. doi: 10.1016/j.cclet.2024.110050
4. [4]
  Peiyan Zhu , Yanyan Yang , Hui Li , Jinhua Wang , Shiqing Li . Rh(Ⅲ)‐Catalyzed sequential ring‐retentive/‐opening [4 + 2] annulations of 2H‐imidazoles towards full‐color emissive imidazo[5,1‐a]isoquinolinium salts and AIE‐active non‐symmetric 1,1′‐biisoquinolines. Chinese Chemical Letters, 2024, 35(10): 109533-. doi: 10.1016/j.cclet.2024.109533
5. [5]
  You Zhou , Li-Sheng Wang , Shuang-Gui Lei , Bo-Cheng Tang , Zhi-Cheng Yu , Xing Li , Yan-Dong Wu , Kai-Lu Zheng , An-Xin Wu . I₂-DMSO mediated tetra-functionalization of enaminones for the construction of novel furo[2′,3′:4,5]pyrimido[1,2-b]indazole skeletons via in situ capture of ketenimine cations. Chinese Chemical Letters, 2025, 36(1): 109799-. doi: 10.1016/j.cclet.2024.109799
6. [6]
  Gaofeng WANG , Shuwen SUN , Yanfei ZHAO , Lixin MENG , Bohui WEI . Structural diversity and luminescence properties of three zinc coordination polymers based on bis(4-(1H-imidazol-1-yl)phenyl)methanone. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 849-856. doi: 10.11862/CJIC.20230479
7. [7]
  Fan JIA , Wenbao XU , Fangbin LIU , Haihua ZHANG , Hongbing FU . Synthesis and electroluminescence properties of Mn²⁺ doped quasi-two-dimensional perovskites (PEA)₂Pb_yMn_1-yBr₄. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1114-1122. doi: 10.11862/CJIC.20230473
8. [8]
  Jinge Zhu , Ailing Tang , Leyi Tang , Peiqing Cong , Chao Li , Qing Guo , Zongtao Wang , Xiaoru Xu , Jiang Wu , Erjun Zhou . Chlorination of benzyl group on the terminal unit of A₂-A₁-D-A₁-A₂ type nonfullerene acceptor for high-voltage organic solar cells. Chinese Chemical Letters, 2025, 36(1): 110233-. doi: 10.1016/j.cclet.2024.110233
9. [9]
  Jingzhao Cheng , Shiyu Gao , Bei Cheng , Kai Yang , Wang Wang , Shaowen Cao . 4-氨基-1H-咪唑-5-甲腈修饰供体-受体型氮化碳光催化剂的构建及其高效光催化产氢研究. Acta Physico-Chimica Sinica, 2024, 40(11): 2406026-. doi: 10.3866/PKU.WHXB202406026
10. [10]
  Qingyun Hu , Wei Wang , Junyuan Lu , He Zhu , Qi Liu , Yang Ren , Hong Wang , Jian Hui . High-throughput screening of high energy density LiMn_1-xFe_xPO₄ via active learning. Chinese Chemical Letters, 2025, 36(2): 110344-. doi: 10.1016/j.cclet.2024.110344
11. [11]
  Guang Xu , Cuiju Zhu , Xiang Li , Kexin Zhu , Hao Xu . Copper-catalyzed asymmetric [4+1] annulation of yne–allylic esters with pyrazolones. Chinese Chemical Letters, 2025, 36(4): 110114-. doi: 10.1016/j.cclet.2024.110114
12. [12]
  Keke Han , Wenjun Rao , Xiuli You , Haina Zhang , Xing Ye , Zhenhong Wei , Hu Cai . Two new high-temperature molecular ferroelectrics [1,5-3.2.2-Hdabcni]X (X = ClO₄⁻, ReO₄⁻). Chinese Chemical Letters, 2024, 35(6): 108809-. doi: 10.1016/j.cclet.2023.108809
13. [13]
  Gangsheng Li , Xiang Yuan , Fu Liu , Zhihua Liu , Xujie Wang , Yuanyuan Liu , Yanmin Chen , Tingting Wang , Yanan Yang , Peicheng Zhang . Three-step synthesis of flavanostilbenes with a 2-cyclohepten-1-one core by Cu-mediated [5 + 2] cycloaddition/decarboxylation cascade. Chinese Chemical Letters, 2025, 36(2): 109880-. doi: 10.1016/j.cclet.2024.109880
14. [14]
  Zhaodong WANG . In situ synthesis, crystal structure, and magnetic characterization of a trinuclear copper complex based on a multi-substituted imidazo[1,5-a]pyrazine scaffold. Chinese Journal of Inorganic Chemistry, 2025, 41(3): 597-604. doi: 10.11862/CJIC.20240268
15. [15]
  Yueying Yang , Huiru Xie , Xinbo Yu , Yang Liu , Hui Wang , Hua Li , Lixia Chen . Design, synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreatic β-cells. Chinese Chemical Letters, 2024, 35(11): 109570-. doi: 10.1016/j.cclet.2024.109570
16. [16]
  Shaonan Liu , Shuixing Dai , Minghua Huang . The impact of ester groups on 1,8-naphthalimide electron transport material in organic solar cells. Chinese Journal of Structural Chemistry, 2024, 43(6): 100277-100277. doi: 10.1016/j.cjsc.2024.100277
17. [17]
  Zhexin Chen , Yuqing Shi , Fang Zhong , Kai Zhang , Furong Zhang , Shenghong Xie , Zhongbin Cheng , Qian Zhou , Yi-You Huang , Hai-Bin Luo . Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects. Chinese Chemical Letters, 2025, 36(4): 109956-. doi: 10.1016/j.cclet.2024.109956
18. [18]
  An Lu , Yuhao Guo , Yi Yan , Lin Zhai , Xiangyu Wang , Weiran Cao , Zijie Li , Zhixia Zhao , Yujie Shi , Yuanjun Zhu , Xiaoyan Liu , Huining He , Zhiyu Wang , Jian-Cheng Wang . Nanomedicine integrating the lipidic derivative of 5-fluorouracil, miriplatin and PD-L1 siRNA for enhancing tumor therapy. Chinese Chemical Letters, 2024, 35(6): 108928-. doi: 10.1016/j.cclet.2023.108928
19. [19]
  Chao LIU , Jiang WU , Zhaolei JIN . Synthesis, crystal structures, and antibacterial activities of two zinc(Ⅱ) complexes bearing 5-phenyl-1H-pyrazole group. Chinese Journal of Inorganic Chemistry, 2024, 40(10): 1986-1994. doi: 10.11862/CJIC.20240153
20. [20]
  Hai-Yang Song , Jun Jiang , Yu-Hang Song , Min-Hang Zhou , Chao Wu , Xiang Chen , Wei-Min He . Supporting-electrolyte-free electrochemical [2 + 2 + 1] annulation of benzo[d]isothiazole 1,1-dioxides, N-arylglycines and paraformaldehyde. Chinese Chemical Letters, 2024, 35(6): 109246-. doi: 10.1016/j.cclet.2023.109246

Get Citation

PDF

XML

Metrics

PDF Downloads(7)
Abstract views(1117)
HTML views(119)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142