Citation: 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[J]. Chinese Chemical Letters, ;2024, 35(11): 109570. doi: 10.1016/j.cclet.2024.109570 shu

Design, synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreatic β-cells

Yueying Yang ^{a, b, 1} ,
Huiru Xie ^{b, 1} ,
Xinbo Yu ^b ,
Yang Liu ^b ,
Hui Wang ^b ,
Hua Li ^{a, b, *,} ,
Lixia Chen ^{b, *,}

a.
Fujian Key Laboratory of Chinese Materia Medica, Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
b.
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China

2022041@fjtcm.edu.cn

syzyclx@163.com

Received Date: 7 November 2023
Revised Date: 24 January 2024
Accepted Date: 26 January 2024
Available Online: 2 February 2024

Figures(4)

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is the most promising target for diabetes treatment by promoting β-cell proliferation. The desmethylbellidifolin (DMB) as a DYRK1A inhibitor could facilitate β-cell proliferation in vivo and in vitro. However, DMB has the problem of weak binding affinity to DYRK1A, which means that continuous high concentration administration of DMB is effective for the diabetes. In order to solve this problem, we designed and synthesized a series of DMB-based proteolysis targeting chimeras (PROTACs) by taking advantage of the property of PROTAC that induce protein degradation in a cycle-catalytic manner. MDM2-based PROTAC X1–4P-MDM2 was identified as the most active PROTAC molecule. Mechanism research showed that X1–4P-MDM2 formed a ternary complex with DYRK1A and murine double minute 2 (MDM2), and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway. At a dose much lower than that of DMB, X1–4P-MDM2 still significantly enhanced β-cell proliferation by inhibiting transforming growth factor beta (TGF-β) and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which may provide a new strategy for the application of DMB in diabetes.
- PROTAC,
- DYRK1A,
- Degraders,
- Desmethylbellidifolin,
- β-Cell proliferation
1. [1]
  M. von Herrath, M. Peakman, B. Roep, Clin. Exp. Immunol. 172 (2013) 186–202. doi: 10.1111/cei.12085
2. [2]
  M.L. Campbell-Thompson, M.A. Atkinson, A.E. Butler, et al., Diabetologia 56 (2013) 2541–2543. doi: 10.1007/s00125-013-3043-5
3. [3]
  P.W. Franks, E. Pearson, J.C. Florez, Diabetes Care 36 (2013) 1413–1421. doi: 10.2337/dc12-2211
4. [4]
  A.E. Butler, J. Janson, S. Bonner-Weir, et al., Diabetes 52 (2003) 102–110. doi: 10.2337/diabetes.52.1.102
5. [5]
  J. Rahier, Y. Guiot, R.M. Goebbels, C. Sempoux, J.C. Henquin, Diabetes Obes. Metab. 10 (Suppl 4) (2008) 32–42. doi: 10.1111/j.1463-1326.2008.00969.x
6. [6]
  A. Vetere, A. Choudhary, S.M. Burns, B.K. Wagner, Nat. Rev. Drug. Discov. 13 (2014) 278–289. doi: 10.1038/nrd4231
7. [7]
  P. Wang, N.M. Fiaschi-Taesch, R.C. Vasavada, et al., Nat. Rev. Endocrinol. 11 (2015) 201–212. doi: 10.1038/nrendo.2015.9
8. [8]
  E. Dirice, D. Walpita, A. Vetere, et al., Diabetes 65 (2016) 1660–1671. doi: 10.2337/db15-1127
9. [9]
  Y. Ogawa, Y. Nonaka, T. Goto, et al., Nat. Commun. 1 (2010) 86. doi: 10.1038/ncomms1090
10. [10]
  W. Shen, M.S. Tremblay, V.A. Deshmukh, et al., J. Am. Chem. Soc. 135 (2013) 1669–1672. doi: 10.1021/ja309304m
11. [11]
  Y.A. Liu, Q. Jin, Q. Ding, et al., Chem. Med. Chem. 15 (2020) 1562–1570. doi: 10.1002/cmdc.202000183
12. [12]
  W. Shen, B. Taylor, Q. Jin, et al., Nat. Commun. 6 (2015) 8372. doi: 10.1038/ncomms9372
13. [13]
  W.R. Goodyer, X. Gu, Y. Liu, et al., Dev. Cell. 23 (2012) 21–34. doi: 10.1016/j.devcel.2012.05.014
14. [14]
  J.J. Heit, A.A. Apelqvist, X. Gu, et al., Nature 443 (2006) 345–349. doi: 10.1038/nature05097
15. [15]
  P. Wang, J.C. Alvarez-Perez, D.P. Felsenfeld, et al., Nat. Med. 21 (2015) 383–388. doi: 10.1038/nm.3820
16. [16]
  K. Kumar, P. Wang, R. Sanchez, et al., J. Med. Chem. 61 (2018) 7687–7699. doi: 10.1021/acs.jmedchem.8b00658
17. [17]
  J.P. Annes, J.H. Ryu, K. Lam, et al., Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 3915–3920. doi: 10.1073/pnas.1201149109
18. [18]
  P.M. Ung, A. Schlessinger, ACS Chem. Biol. 10 (2015) 269–278. doi: 10.1021/cb500696t
19. [19]
  Y. Abdolazimi, Z. Zhao, S. Lee, et al., Endocrinology 159 (2018) 3143–3157. doi: 10.1210/en.2018-00083
20. [20]
  T.M. Horton, P.A. Allegretti, S. Lee, et al., Cell. Chem. Biol. 26 (2019) 213–222. doi: 10.1016/j.chembiol.2018.10.019
21. [21]
  M. Debdab, F. Carreaux, S. Renault, et al., J. Med. Chem. 54 (2011) 4172–4186. doi: 10.1021/jm200274d
22. [22]
  M. Zheng, Q. Zhang, C. Zhang, et al., Clin. Transl. Med. 11 (2021) e494. doi: 10.1002/ctm2.494
23. [23]
  C. Wang, Y. Zhang, T. Zhang, et al., J. Enzyme. Inhib. Med. Chem. 37 (2022) 1667–1693. doi: 10.1080/14756366.2022.2076675
24. [24]
  J. Gao, L. Yang, S. Lei, et al., Sci. Bull. 68 (2023) 1069–1085. doi: 10.1016/j.scib.2023.04.028
25. [25]
  Y. Wu, Y. Yang, W. Wang, et al., Acta. Pharm. Sin. B 12 (2022) 4262–4265. doi: 10.1016/j.apsb.2022.07.007
26. [26]
  J. Wu, W.H. Wang, C.H. Leung, Acta Materia Med. 2 (2023) 42–53.
27. [27]
  D.P. Bondeson, A. Mares, I.E. Smith, et al., Nat. Chem. Biol. 11 (2015) 611–617. doi: 10.1038/nchembio.1858
28. [28]
  E.S. Fischer, K. Böhm, J.R. Lydeard, et al., Nature 512 (2014) 49–53. doi: 10.1038/nature13527
29. [29]
  Y.H. Sun, X. Luo, Z.M. Yang, et al., Chin. Chem. Lett. 34 (2023) 107924. doi: 10.1016/j.cclet.2022.107924
30. [30]
  S. Khan, X. Zhang, D. Lv, et al., Nat. Med. 25 (2019) 1938–1947. doi: 10.1038/s41591-019-0668-z
31. [31]
  X. Han, W.Y. Wei, Y. Sun, Acta Materia Medica 1 (2022) 244–259.
32. [32]
  Y. Liu, M. Zheng, Z. Ma, et al., Chin. Chem. Lett. 34 (2023) 107762. doi: 10.1016/j.cclet.2022.107762
33. [33]
  L.Y. Zhao, X. Xiong, L. Liu, et al., Chin. Chem. Lett. 33 (2022) 1841–1849. doi: 10.3390/biology11121841
34. [34]
  K. Kumar, C. Suebsuwong, P. Wang, et al., J. Med. Chem. 64 (2021) 2901–2922. doi: 10.1021/acs.jmedchem.0c02050
35. [35]
  K. Li, C.M. Crews, Chem. Soc. Rev. 51 (2022) 5214–5236. doi: 10.1039/d2cs00193d
36. [36]
  D. Chirnomas, K.R. Hornberger, C.M. Crews, Nat. Rev. Clin. Oncol. 20 (2023) 265–278. doi: 10.1038/s41571-023-00736-3
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