Citation: Hui Lei, Yingying Jiang, Jiayu Liu, Weifeng Zhang, Fanbo Meng, Jun Mou, Wenyi Liu, Pengcheng Lei, Rui Xiong, Zan Xu, Hang Zhang, Yanjun Wang, Guo-Bo Li, Lingling Yang, Hua-Li Wang. Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer[J]. Chinese Chemical Letters, ;2026, 37(6): 111511. doi: 10.1016/j.cclet.2025.111511 shu

Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer

Hui Lei ^{a, b, 1} ,
Yingying Jiang ^{a, 1} ,
Jiayu Liu ^a ,
Weifeng Zhang ^a ,
Fanbo Meng ^c ,
Jun Mou ^c ,
Wenyi Liu ^a ,
Pengcheng Lei ^a ,
Rui Xiong ^a ,
Zan Xu ^a ,
Hang Zhang ^a ,
Yanjun Wang ^a ,
Guo-Bo Li ^c ,
Lingling Yang ^{a, *,} ,
Hua-Li Wang ^{b, *,}

a.
College of Food and Bioengineering, Xihua University, Chengdu 610039, China
b.
Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
c.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China

yangll080808@sina.com

yangll@mail.xhu.edu.cn

wanghuali_1992@163.com

Received Date: 15 March 2025
Revised Date: 24 June 2025
Accepted Date: 25 June 2025
Available Online: 1 July 2025

Figures(4)

Glutaminyl cyclase (QC), a key enzyme catalyzing the pyroglutamate modification of bioactive peptides, has emerged as a promising pharmacological target in cancer and other human diseases. Inhibition of QC activity represents a potential therapeutic strategy for diseases associated with QC dysregulation, suggesting that QC inhibitors might be as promising therapeutic approach for these diseases. Building upon our previous lead compound 1 (half maximal inhibitory concentration (IC₅₀): Golgi resident QC (gQC), 3.22 µmol/L; secretory QC (sQC), 4.04 µmol/L), we performed systematic structural optimization to develop novel 3,4-disubstituted indole-2-ketone derivatives. Structure-activity relationship (SAR) studies identified highly active gQC and sQC inhibitors (compounds 24, 28, and 29) with significantly enhanced QC inhibitory activity. Among them, 28 exhibited superior inhibitory activity against gQC (IC₅₀ = 0.095 µmol/L) compared to sQC (IC₅₀ = 1.33 µmol/L), and could most significantly improve the thermal stability of gQC protein. Using compound 17 with similar structure but 130 times lower gQC inhibitory activity than 28 as a negative control, the in vitro anti-tumor activity study found that 28 can bind to gQC in MDA-MB-231 breast cancer cells and significantly inhibit the growth and migration, by affecting cell proliferation and inducing G0/G1 phase cell cycle arrest. In nude mice bearing MDA-MB-231 cell xenograft, intratumor injection of 28 (25 mg/kg) produced 40.6% inhibition rates. This work not only provides structural basis and new leads for drug discovery targeting QC, but also presents compelling evidence supporting QC, especially gQC as a potential target for breast cancer therapy.
- Glutaminyl cyclase,
- Qc inhibitor,
- Structure-activity relationship,
- Cancer,
- MDA-MB-231 cell
1. [1]
  R. Barreira da Silva, R.M. Leitao, X. Pechuan-Jorge, et al., Nat. Immunol. 23 (2022) 568–580. doi: 10.1038/s41590-022-01153-x
2. [2]
  D.K. Vijayan, K.Y.J. Zhang, Pharmacol. Res. 147 (2019) 104342. doi: 10.1016/j.phrs.2019.104342
3. [3]
  C. Xu, Y.N. Wang, H. Wu, J. Med. Chem. 64 (2021) 6549–6565. doi: 10.1021/acs.jmedchem.1c00325
4. [4]
  J.R.M. Coimbra, P.I. Moreira, A.E. Santos, J.A.R. Salvador, Drug Discov. Today 28 (2023) 103644. doi: 10.1016/j.drudis.2023.103644
5. [5]
  A. Stephan, M. Wermann, A. von Bohlen, et al., FEBS J. 276 (2009) 6522–6536. doi: 10.1111/j.1742-4658.2009.07337.x
6. [6]
  G. Tassone, C. Pozzi, S. Mangani, Int. J. Mol. Sci. 25 (2024) 8279. doi: 10.3390/ijms25158279
7. [7]
  S. Schilling, U. Zeitschel, T. Hoffmann, et al., Nat. Med. 14 (2008) 1106–1111. doi: 10.1038/nm.1872
8. [8]
  N. Van Manh, V.H. Hoang, V.T.H. Ngo, et al., Eur. J. Med. Chem. 244 (2022) 114837. doi: 10.1016/j.ejmech.2022.114837
9. [9]
  Z. Wang, B. Sun, F. Zhu, Fish Shellf. Immunol. 78 (2018) 299–309. doi: 10.1016/j.fsi.2018.04.059
10. [10]
  M.E.W. Logtenberg, J.H.M. Jansen, M. Raaben, et al., Nat. Med. 25 (2019) 612–619. doi: 10.1038/s41591-019-0356-z
11. [11]
  Z. Wu, Q. Lamao, M. Gu, et al., Cell. Mol. Immunol. 21 (2024) 362–373. doi: 10.1038/s41423-024-01135-z
12. [12]
  L. Yu, P. Zhao, Y. Sun, et al., Signal Transduct. Target. Ther. 8 (2023) 454. doi: 10.1038/s41392-023-01715-x
13. [13]
  Y. Liu, S. Lu, Y. Sun, et al., Front. Immunol. 14 (2023) 1166377. doi: 10.3389/fimmu.2023.1166377
14. [14]
  K. Müller, F. Vogiatzi, D. Winterberg, et al., Blood 140 (2022) 45–57. doi: 10.1182/blood.2021014485
15. [15]
  Y. Zhang, Y. Wang, Z. Zhao, et al., Eur. J. Pharmacol. 931 (2022) 175178. doi: 10.1016/j.ejphar.2022.175178
16. [16]
  M. Hartlage-Rübsamen, A. Bluhm, S. Moceri, et al., Acta Neuropathol. 142 (2021) 399–421. doi: 10.1007/s00401-021-02349-5
17. [17]
  M. Jimenez-Sanchez, W. Lam, M. Hannus, et al., Nat. Chem. Biol. 11 (2015) 347–354. doi: 10.1038/nchembio.1790
18. [18]
  K. Szczęśniak, F. Veillard, C. Scavenius, et al., mBio 14 (2023) e0098023. doi: 10.1128/mbio.00980-23
19. [19]
  D. Ramsbeck, N. Taudte, N. Jänckel, et al., Pharmaceuticals 14 (2021) 1206. doi: 10.3390/ph14121206
20. [20]
  M. Hartlage-Rübsamen, A. Waniek, J. Meissner, et al., Acta Neuropathol. 129 (2015) 565–583. doi: 10.1007/s00401-015-1395-2
21. [21]
  X. Wang, L. Wang, X. Yu, et al., Int. Immunopharmacol. 75 (2019) 105770. doi: 10.1016/j.intimp.2019.105770
22. [22]
  G. Riccio, D. De Luca, C. Lauritano, Mar. Drug 18 (2020) 237. doi: 10.3390/md18050237
23. [23]
  Z. Wu, L. Weng, T. Zhang, et al., Cell Res. 29 (2019) 502–505. doi: 10.1038/s41422-019-0177-0
24. [24]
  X. Chen, X. Yu, Y. Cui, et al., J. Proteom. Res. 23 (2024) 1859–1870. doi: 10.1021/acs.jproteome.4c00197
25. [25]
  A. Kehlen, M. Haegele, K. Menge, et al., Endocr. Relat. Cancer 20 (2013) 79–90.
26. [26]
  Y.L. Chen, K.F. Huang, W.C. Kuo, et al., Biochem. J. 442 (2012) 403–412. doi: 10.1042/BJ20110535
27. [27]
  J.R.M. Coimbra, J.A.R. Salvador, Expert Opin. Ther. Pat. 31 (2021) 809–836. doi: 10.1080/13543776.2021.1917549
28. [28]
  W.J. Behof, J.R. Haynes, C.A. Whitmore, et al., ACS Sens. 9 (2024) 2605–2613. doi: 10.1021/acssensors.4c00313
29. [29]
  K.V. Dileep, N. Sakai, K. Ihara, et al., Int. J. Biol. Macromol. 170 (2021) 415–423. doi: 10.1016/j.ijbiomac.2020.12.118
30. [30]
  M. Li, Y. Dong, X. Yu, et al., Bioorg. Med. Chem. 24 (2016) 2280–2286. doi: 10.1016/j.bmc.2016.03.064
31. [31]
  C. Pozzi, F. Di Pisa, M. Benvenuti, S. Mangani, J. Biol. Inorg. Chem. 23 (2018) 1219–1226. doi: 10.1007/s00775-018-1605-1
32. [32]
  Y. Xie, C. Chen, S. Lin, et al., Eur. J. Med. Chem. 248 (2023) 115089. doi: 10.1016/j.ejmech.2023.115089
33. [33]
  D. Chen, Q. Chen, X. Qin, et al., Front. Aging Neurosci. 15 (2023) 1209863. doi: 10.3389/fnagi.2023.1209863
34. [34]
  J. Mou, X.L. Ning, X.Y. Wang, et al., J. Med. Chem. 67 (2024) 8730–8756. doi: 10.1021/acs.jmedchem.4c00049
35. [35]
  P. Scheltens, M. Hallikainen, T. Grimmer, et al., Alzheimer. Res. Ther. 10 (2018) 107. doi: 10.1186/s13195-018-0431-6
36. [36]
  E.G.B. Vijverberg, T.M. Axelsen, A.R. Bihlet, et al., Alzheimer. Res. Ther. 13 (2021) 142. doi: 10.1186/s13195-021-00882-9
37. [37]
  Q. Gong, J. Song, Y. Song, et al., Chin. Chem. Lett. 36 (2025) 110456. doi: 10.1016/j.cclet.2024.110456
38. [38]
  Z. Hongcai, Z. Zhengbing, L. Wenhua, et al., Tetrahedron Lett. 83 (2021) 153426. doi: 10.1016/j.tetlet.2021.153426
39. [39]
  Q. Zhang, Y. Fu, H.W. Wang, et al., Chin. Chem. Lett. 19 (2007) 281–285.
40. [40]
  P.X. Xiao, Zhen, J.I.A.O. Xiao, Tian LIANG, et al., Chin. Chem. Lett. 14 (2003) 667–669.
41. [41]
  K. Wu, X. Ruan, S. Jia, et al., Chin. Chem. Lett. 35 (2024) 110646.
42. [42]
  B. Lomenick, R. Hao, N. Jonai, et al., Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 21984–21989. doi: 10.1073/pnas.0910040106
43. [43]
  A. Daina, O. Michielin, V. Zoete, Sci. Rep. 7 (2017) 42717. doi: 10.1038/srep42717
44. [44]
  T. Lammers, P. Peschke, R. Kühnlein, et al., Neoplasia 8 (2006) 788–795. doi: 10.1593/neo.06436
45. [45]
  M.R. Shah, C.L. Kriedt, N.H. Lents, et al., J. Exp. Clin. Cancer Res. 28 (2009) 84. doi: 10.1186/1756-9966-28-84
46. [46]
  C.M. Springate, J.K. Jackson, M.E. Gleave, H.M. Burt, Cancer Chemother. Pharmacol. 56 (2005) 239–247. doi: 10.1007/s00280-004-0997-5
47. [47]
  K.P. Fabian, G. Santiago-Sanchez, M.R. Padget, et al., J. Immunother. Cancer 12 (2024) e009712. doi: 10.1136/jitc-2024-009712
1. [1]
  Hao Cai , Xiaoyan Wu , Lei Jiang , Feng Yu , Yuxiang Yang , Yan Li , Xian Zhang , Jian Liu , Zijian Li , Hong Bi . Lysosome-targeted carbon dots with a light-controlled nitric oxide releasing property for enhanced photodynamic therapy. Chinese Chemical Letters, 2024, 35(4): 108946-. doi: 10.1016/j.cclet.2023.108946
2. [2]
  Qin Cheng , Ming Huang , Qingqing Ye , Bangwei Deng , Fan Dong . Indium-based electrocatalysts for CO₂ reduction to C1 products. Chinese Chemical Letters, 2024, 35(6): 109112-. doi: 10.1016/j.cclet.2023.109112
3. [3]
  A-Yang Wang , Sheng-Hua Zhou , Mao-Yin Ran , Xin-Tao Wu , Hua Lin , Qi-Long Zhu . Regulating the key performance parameters for Hg-based IR NLO chalcogenides via bandgap engineering strategy. Chinese Chemical Letters, 2024, 35(10): 109377-. doi: 10.1016/j.cclet.2023.109377
4. [4]
  Anjing Liao , Wei Sun , Yaming Liu , Han Yan , Zhi Xia , Jian Wu . Pyrrole and pyrrolidine analogs: The promising scaffold in discovery of pesticides. Chinese Chemical Letters, 2025, 36(3): 110094-. doi: 10.1016/j.cclet.2024.110094
5. [5]
  Yi-Ru Bai , Qing-Chuan Duan , Dong-Jie Seng , Ying Xu , Hong-Bo Ren , Jie Zhang , Dan-Dan Shen , Li Yang , Hong-Min Liu , Shuo Yuan . A comprehensive review of small molecule drugs approved by the FDA in 2024: Advance and prospect. Chinese Chemical Letters, 2025, 36(10): 111025-. doi: 10.1016/j.cclet.2025.111025
6. [6]
  Haoran Xu , Jiaqi Fan , Jiwei Liu , Qi Wei , Ruoshui Li , Pengcheng Yuan , Bing Xiao , Ying Piao , Wenjing Sun , Jiajia Xiang , Shiqun Shao , Zhuxian Zhou , Youqing Shen , Nigel K.H. Slater , Jianbin Tang . Tetra-branched ionizable lipids enhance the stability and transfection efficiency of lipid nanoparticles for mRNA delivery. Chinese Chemical Letters, 2025, 36(11): 110833-. doi: 10.1016/j.cclet.2025.110833
7. [7]
  Qi Wang , Yicong Gao , Feng Lu , Quli Fan . Preparation and Performance Characterization of the Second Near-Infrared Phototheranostic Probe: A New Design and Teaching Practice of Polymer Chemistry Comprehensive Experiment. University Chemistry, 2024, 39(11): 342-349. doi: 10.12461/PKU.DXHX202404141
8. [8]
  Ruizhi Duan , Xiaomei Wang , Panwang Zhou , Yang Liu , Can Li . The role of hydroxyl species in the alkaline hydrogen evolution reaction over transition metal surfaces. Acta Physico-Chimica Sinica, 2025, 41(9): 100111-0. doi: 10.1016/j.actphy.2025.100111
9. [9]
  Haiying Jiang , Liuhong Song , Yangyang Cheng , Kefen Yue , Mingli Peng , Huilin Guo . Ph―C≡C―Cu_2.5的力致变色现象探究——推荐一个物理化学实验. University Chemistry, 2025, 40(8): 249-254. doi: 10.12461/PKU.DXHX202410003
10. [10]
  Yiran Tao , Chunlei Dai , Zhaoxiang Xie , Xinru You , Kaiwen Li , Jun Wu , Hai Huang . Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer. Chinese Chemical Letters, 2024, 35(8): 109170-. doi: 10.1016/j.cclet.2023.109170
11. [11]
  Weifei Zhang , Danfeng Xu , Jinru Tian , Ying Kan , Xuanlin Feng , Jia Liu , Hongmei Li , Nan Li . An inverse opal structure-based human alveolar lung-on-a-chip for the study of Osimertinib treatment in non-small cell lung cancer. Chinese Chemical Letters, 2026, 37(4): 111453-. doi: 10.1016/j.cclet.2025.111453
12. [12]
  Yongjian Jiang , Feng Cheng , Jun Zhou , Lei Zhan , Chunmei Li , Chengzhi Huang . Regulation of cancer cell apoptosis with DNA nanocalculator. Chinese Chemical Letters, 2026, 37(1): 110071-. doi: 10.1016/j.cclet.2024.110071
13. [13]
  Jia Chen , Yun Liu , Zerong Long , Yan Li , Hongdeng Qiu . Colorimetric detection of α-glucosidase activity using Ni-CeO₂ nanorods and its application to potential natural inhibitor screening. Chinese Chemical Letters, 2024, 35(9): 109463-. doi: 10.1016/j.cclet.2023.109463
14. [14]
  Yang Liu , Yan Liu , Kaiyin Yang , Zhiruo Zhang , Wenbo Zhang , Bingyou Yang , Hua Li , Lixia Chen . A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2. Chinese Chemical Letters, 2024, 35(8): 109264-. doi: 10.1016/j.cclet.2023.109264
15. [15]
  Boran Cheng , Lei Cao , Chen Li , Fang-Yi Huo , Qian-Fang Meng , Ganglin Tong , Xuan Wu , Lin-Lin Bu , Lang Rao , Shubin Wang . Fluorine-doped carbon quantum dots with deep-red emission for hypochlorite determination and cancer cell imaging. Chinese Chemical Letters, 2024, 35(6): 108969-. doi: 10.1016/j.cclet.2023.108969
16. [16]
  Jing Chen , Peisi Xie , Pengfei Wu , Yu He , Zian Lin , Zongwei Cai . MALDI coupled with laser-postionization and trapped ion mobility spectrometry contribute to the enhanced detection of lipids in cancer cell spheroids. Chinese Chemical Letters, 2024, 35(4): 108895-. doi: 10.1016/j.cclet.2023.108895
17. [17]
  Yuanzheng Wang , Chen Zhang , Shuyan Han , Xiaoli Kong , Changyun Quan , Jun Wu , Wei Zhang . Cancer cell membrane camouflaged biomimetic gelatin-based nanogel for tumor inhibition. Chinese Chemical Letters, 2024, 35(11): 109578-. doi: 10.1016/j.cclet.2024.109578
18. [18]
  Zhi Li , Shuya Pan , Yuan Tian , Shaowei Liu , Weifeng Wei , Jinlin Wang , Tianfeng Chen , Ling Wang . Selenium nanoparticles enhance the chemotherapeutic efficacy of pemetrexed against non-small cell lung cancer. Chinese Chemical Letters, 2024, 35(12): 110018-. doi: 10.1016/j.cclet.2024.110018
19. [19]
  Yanfei Liu , Yaqin Hu , Yifu Tan , Qiwen Chen , Zhenbao Liu . Tumor acidic microenvironment activatable DNA nanostructure for precise cancer cell targeting and inhibition. Chinese Chemical Letters, 2025, 36(1): 110289-. doi: 10.1016/j.cclet.2024.110289
20. [20]
  Yanjun Cai , Yong Jiang , Yu Chen , Erzhuo Cheng , Yuan Gu , Yuwei Li , Qianqian Liu , Jian Zhang , Jifang Liu , Shisong Han , Bin Yang . Amplifying STING activation and immunogenic cell death by metal-polyphenol coordinated nanomedicines for enhanced cancer immunotherapy. Chinese Chemical Letters, 2025, 36(5): 110437-. doi: 10.1016/j.cclet.2024.110437

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(18)
HTML views(2)

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