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
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