Citation: Jinpeng Wang, Min Zhang, Susheng Liu, Zhipeng He, Rui Wang, Minchan Liang, Yuhao An, Chenran Jiang, Chunli Song, Zigong Ning, Feng Yin, Hao Huang, Zigang Li, Yuxin Ye. Targeting UBE2C for degradation by bioPROTACs based on bacterial E3 ligase[J]. Chinese Chemical Letters, ;2023, 34(4): 107732. doi: 10.1016/j.cclet.2022.08.012 shu

Targeting UBE2C for degradation by bioPROTACs based on bacterial E3 ligase

Jinpeng Wang ^{a, 1} ,
Min Zhang ^{b, 1} ,
Susheng Liu ^b ,
Zhipeng He ^b ,
Rui Wang ^b ,
Minchan Liang ^b ,
Yuhao An ^b ,
Chenran Jiang ^b ,
Chunli Song ^b ,
Zigong Ning ^c ,
Feng Yin ^b ,
Hao Huang ^{a, *,} ,
Zigang Li ^{a, b, *,} ,
Yuxin Ye ^{b, *,}

a.
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
b.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518055, China
c.
School of Civil and Environmental Engineering, Harbin Institute of Technology, Shenzhen 518055, China

huang.hao@pku.edu.cn

lizg@pkusz.edu.cn

yeyx@szbl.ac.cn

Received Date: 19 March 2022
Revised Date: 2 August 2022
Accepted Date: 8 August 2022
Available Online: 10 August 2022

Figures(4)

UBE2C (Ubiquitin conjugating enzyme E2 C), a key regulator of cell cycle progression, is a promising target for discovery of antitumor agents. However, it is challenging to develop inhibitors of UBE2C owing to its lack of “druggable” pockets. BioPROTACs (biological proteolysis targeting chimeras) are a kind of protein-based degraders by fusing an adaptor to a subunit of E3 ligase for ubiquitination and subsequent proteasome-dependent degradation of target protein. We report herein the design and biological evaluation of a UBE2C-targeting bioPROTAC based on the NEL (novel E3 ligase) domain of bacterial E3 ligase IpaH9.8 and the UBE2C-binding WHB (winged-helix B) domain of APC2 (anaphase promoting complex subunit 2). The in vitro ubiquitination test and Mass Spectrometry analysis showed that the bioPROTAC could transfer ubiquitin to surface exposed lysines on UBE2C and catalyzed the formation of polyubiquitin chains. In addition, the transient co-expression experiment showed that the bioPROTAC could promote proteasomal degradation of heterologous UBE2C and rescue its downstream substrates in mammalian cells.
- UBE2C,
- IpaH9.8,
- BioPROTAC,
- Ubiquitination,
- Degradation,
- Linker optimization
1. [1]
  Y. Lin, W.C. Hwang, R. Basavappa, J. Biol. Chem. 277 (2002) 21913–21921. doi: 10.1074/jbc.M109398200
2. [2]
  Y. Okamoto, T. Ozaki, K. Miyazaki, et al., Cancer Res. 63 (2003) 4167–4173.
3. [3]
  C. Alfieri, L. Chang, Z. Zhang, et al., Nature 536 (2016) 431–436. doi: 10.1038/nature19083
4. [4]
  L. Chang, Z. Zhang, J. Yang, S.H. McLaughlin, D. Barford, Nature 522 (2015) 450–454. doi: 10.1038/nature14471
5. [5]
  L.F. Chang, Z. Zhang, J. Yang, S.H. McLaughlin, D. Barford, Nature 513 (2014) 388–393. doi: 10.1038/nature13543
6. [6]
  Q. Li, L. Chang, S. Aibara, et al., Proc. Natl. Acad. Sci. USA 113 (2016) 10547–10552. doi: 10.1073/pnas.1607147113
7. [7]
  Z. Shen, X. Jiang, C. Zeng, et al., BMC Cancer 13 (2013) 192. doi: 10.1186/1471-2407-13-192
8. [8]
  R. Wang, Y. Song, X. Liu, et al., Int. J. Oncol. 50 (2017) 1116–1126. doi: 10.3892/ijo.2017.3880
9. [9]
  I. Presta, F. Novellino, A. Donato, et al., Int. J. Mol. Sci. 21 (2020) 1115 doi: 10.3390/ijms21031115
10. [10]
  M.D. Stewart, T. Ritterhoff, R.E. Klevit, P.S. Brzovic, Cell Res. 26 (2016) 423–440. doi: 10.1038/cr.2016.35
11. [11]
  A. Poso, J. Med. Chem. 64 (2021) 10680–10681. doi: 10.1021/acs.jmedchem.1c01126
12. [12]
  M. Bekes, D.R. Langley, C.M. Crews, Nat. Rev. Drug Discov. 21 (2022) 181–200. doi: 10.1038/s41573-021-00371-6
13. [13]
  M. Pettersson, C.M. Crews, Drug Discov. Today Technol. 31 (2019) 15–27. doi: 10.1016/j.ddtec.2019.01.002
14. [14]
  M.B. Ludwicki, J. Li, E.A. Stephens, et al., ACS Cent. Sci. 5 (2019) 852–866. doi: 10.1021/acscentsci.9b00127
15. [15]
  S. Lim, R. Khoo, K.M. Peh, et al., Proc. Natl. Acad. Sci. USA 117 (2020) 5791–5800. doi: 10.1073/pnas.1920251117
16. [16]
  F. Cong, J. Zhang, W. Pao, P. Zhou, H. Varmus, BMC Mol. Biol. 4 (2003) 10. doi: 10.1186/1471-2199-4-10
17. [17]
  Y. Su, S. Ishikawa, M. Kojima, B. Liu, Proc. Natl. Acad. Sci. USA 100 (2003) 12729–12734. doi: 10.1073/pnas.2133261100
18. [18]
  Y. Ma, Y. Gu, Q. Zhang, et al., Mol. Cancer Ther. 12 (2013) 286–294. doi: 10.1158/1535-7163.MCT-12-0650
19. [19]
  S. Lim, R. Khoo, Y.C. Juang, et al., ACS Cent. Sci. 7 (2021) 274–291. doi: 10.1021/acscentsci.0c01337
20. [20]
  K.W. Teng, S.T. Tsai, T. Hattori, et al., Nat. Commun. 12 (2021) 2656. doi: 10.1038/s41467-021-22969-5
21. [21]
  S. Hatakeyama, M. Watanabe, Y. Fujii, K.I. Nakayama, Cancer Res. 65 (2005) 7874–7879. doi: 10.1158/0008-5472.CAN-05-1581
22. [22]
  P. Zhou, R. Bogacki, L. McReynolds, P.M. Howley, Mol. Cell 6 (2000) 751–756. doi: 10.1016/S1097-2765(00)00074-5
23. [23]
  X. Li, L. Shen, J. Zhang, et al., Cancer Res. 67 (2007) 8716–8724. doi: 10.1158/0008-5472.CAN-06-3731
24. [24]
  E. Caussinus, O. Kanca, M. Affolter, Nat. Struct. Mol. Biol. 19 (2011) 117–121.
25. [25]
  L.J. Fulcher, T. Macartney, P. Bozatzi, et al., Open Bio. 6 (2016) 160255. doi: 10.1098/rsob.160255
26. [26]
  L.J. Fulcher, L.D. Hutchinson, T.J. Macartney, C. Turnbull, G.P. Sapkota, Open Biol 7 (2017) 170066. doi: 10.1098/rsob.170066
27. [27]
  M.R. Baltz, E.A. Stephens, M.P. Delisa, Curr. Protoc. Chem. Biol. 10 (2018) 72–90. doi: 10.1002/cpch.37
28. [28]
  Y. Ye, Y. Xiong, H. Huang, Commun. Biol. 3 (2020) 752. doi: 10.1038/s42003-020-01492-1
29. [29]
  N.G. Brown, R. Vanderlinden, E.R. Watson, et al., Proc. Natl. Acad. Sci. USA 112 (2015) 5272–5279. doi: 10.1073/pnas.1504161112
30. [30]
  E.R. Watson, C.R.R. Grace, W. Zhang, et al., Proc. Natl. Acad. Sci. USA 116 (2019) 17280–17289. doi: 10.1073/pnas.1902889116
31. [31]
  J. Jumper, R. Evans, A. Pritzel, et al., Nature 596 (2021) 583–589. doi: 10.1038/s41586-021-03819-2
32. [32]
  D.J. Edwards, F.C. Streich, Jr., V.P. Ronchi, D.R. Todaro, A.L. Haas, J. Biol. Chem. 289 (2014) 34114–34128. doi: 10.1074/jbc.M114.609164
33. [33]
  A.D. Portnoff, E.A. Stephens, J.D. Varner, M.P. DeLisa, J. Biol. Chem. 289 (2014) 7844–7855. doi: 10.1074/jbc.M113.544825
34. [34]
  N.D. Udeshi, T. Svinkina, P. Mertins, et al., Mol. Cell Proteomics 12 (2013) 825–831. doi: 10.1074/mcp.O112.027094
35. [35]
  V. Akimov, I. Barrio-Hernandez, S.V.F. Hansen, et al., Nat. Struct. Mol. Biol. 25 (2018) 631–640. doi: 10.1038/s41594-018-0084-y
36. [36]
  P. Beltrao, V. Albanese, L.R. Kenner, et al., Cell 150 (2012) 413–425. doi: 10.1016/j.cell.2012.05.036
37. [37]
  A. Stukalov, V. Girault, V. Grass, et al., Nature 594 (2021) 246–252. doi: 10.1038/s41586-021-03493-4
38. [38]
  I. Gasic, B.J. Groendyke, R.P. Nowak, et al., Cells 9 (2020) 1083. doi: 10.3390/cells9051083
39. [39]
  H. Zhang, Y. Han, Y. Yang, et al., J. Am. Chem. Soc. 143 (2021) 16377–16382. doi: 10.1021/jacs.1c08521
40. [40]
  H. Xu, X. Qin, Y. Zhang, et al., Chin. Chem. Lett. 33 (2022) 2001–2004. doi: 10.1016/j.cclet.2021.09.071
41. [41]
  Q. Bi, X. Song, A. Hu, et al., Chin. Chem. Lett. 31 (2020) 3041–3046. doi: 10.1016/j.cclet.2020.07.030
42. [42]
  R. Liu, C. Luo, Z. Pang, et al., Chin. Chem. Lett. 34 (2023) 107518. doi: 10.1016/j.cclet.2022.05.032
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