Citation: Dong Haoran, Subiding Tayier, Wang Xin, Lei Xiaoguang. Research Progress of Covalent Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2018, 38(9): 2296-2306. doi: 10.6023/cjoc201804018 shu

Research Progress of Covalent Inhibitors

a.
Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871
b.
Peking-Tsinghua Center for Life Sciences, Beijing 100871

Corresponding author: Lei Xiaoguang, xglei@pku.edu.cn
Received Date: 10 April 2018
Revised Date: 19 June 2018
Available Online: 24 September 2018
Fund Project: the National Key Fundamental Research and Development of China (973 Program) 2015CB856200the National Key Research and Development Program of China 2017YFA0505200the National Natural Science Foundation of China 21625201the National Natural Science Foundation of China 21521003Project supported by the National Key Research and Development Program of China (No. 2017YFA0505200), the National Key Fundamental Research and Development of China (973 Program, No. 2015CB856200), the National Natural Science Foundation of China (Nos. 21472010, 21521003, 21561142002, 21625201)the National Natural Science Foundation of China 21472010the National Natural Science Foundation of China 21561142002

Figures(8)

The development of covalent inhibitors plays a major role in recent drug discovery due to their potential excellent pharmacokinetics. Covalent inhibitors are small organic molecules which interact with specific target proteins and form a covalent bond, resulting an alteration of the protein conformation and subsequently inhibit the protein activity. The modifications of proteins by covalent inhibitors are generally irreversible with some exceptions. In this review, the commercial covalent inhibitors that interact with proteins via Michael additions, nucleophilic substitution, or disulfide linkage are reviewed. The discussion on various types of warheads in covalent inhibitors could inspire future rational drug design.
- covalent inhibitors,
- warheads,
- drug design
1. [1]
  Zhang, Y. K.; Lei, J. P.; Xie, D. Q. J. Am. Chem. Soc. 2015, 137, 70. doi: 10.1021/ja5112964
2. [2]
  Andrieu, J. P.; Guilmi, A. M. D.; Mouz, N.; Hoskins, J.; Jaskunas, S. R.; Gagnon, J.; Dideberg, O.; Vernet, T. J. Bacteriol. 1998, 180, 5652.
3. [3]
  Aronson, J. K. Meyler's Side Effects of Drugs, Elsevier Science, Amsterdam, 2016, p. 382.
4. [4]
  Drahl, C.; Cravatt, B. F.; Sorensen, E. J. Angew. Chem. Int. Ed. 2005, 44, 5788. doi: 10.1002/(ISSN)1521-3773
5. [5]
  Lu, L.; Michael, M.; Gu, Z. L.; Zhang, W. P. Sci. Rep. 2015, 5, 8783. doi: 10.1038/srep08783
6. [6]
  Clement, L. L.; Tsakos, M.; Schaffert, E. S.; Scavenius, C.; Enghild, J. J.; Poulsen, T. B. Chem. Commun. 2015, 51, 12427. doi: 10.1039/C5CC04500B
7. [7]
  Uesugi, S.; Fujisawa, N.; Yoshida, J.; Watanabe, M.; Dan, S.; Yamori, T.; Shiono, Y.; Kimura, K. J. Antibiot. 2016, 69, 133.
8. [8]
  Albrecht, A.; Albrecht, L.; Janecki, T. Eur. J. Org. Chem. 2011, 2011, 2747.
9. [9]
  (a) Walker, E. H.; Pacold, M. E.; Perisic, O. Mol. Cell. 2000, 6, 909.
  (b) Sorensen, E. J.; Drahl, C.; Cravatt, B. F. Angew. Chem., Int. Ed. 2005, 44, 5788.
10. [10]
  Bauman, J. E.; Jimeno, A.; Weissman, C.; Adkins, D.; Schnadig, I.; Beauregard, P.; Bowles, D. W.; Spira, A.; Levy, B.; Seetharamu, N.; Hausman, D.; Walker, L.; Rudin, C. M.; Shirai, K. Oral Oncol. 2015, 51, 383.
11. [11]
  Jones, J. B.; Middleton, H. W. Can. J. Chem. 1970, 48, 3819.
12. [12]
  Csuk, R.; Schwarz, S.; Siewert, B.; Kluge, R.; Strohl, D. Arch. Pharm. 2012, 345, 215. doi: 10.1002/ardp.v345.3
13. [13]
  (a) Lei, X. G.; Yu, X. L.; Li, C. Org. Lett. 2010, 12, 4284.
  (b) Lei, X. G.; Dong, T.; Li, C.; Wang, X.; Dian, L. Y.; Zhang, X. G.; Li. L.; Chen, S.; Cao, R.; Li, L.; Huang, N.; He, S. D. Nat. Commum. 2015, 6, 6522.
14. [14]
  Wei, L.; Wu, J.; Li, G.; Shi, N. Curr. Pharm. Des. 2012, 18, 1186. doi: 10.2174/138161212799436395
15. [15]
  Díez-Dacal, B.; Perez-Sala, D. Cancer Lett. 2012, 320, 150.
16. [16]
  Grill, S. P.; Leung, C. H.; Lam, W.; Han, Q. B.; Sun, H. D.; Cheng, Y. C. Mol. Pharmacol. 2006, 70, 1946.
17. [17]
  Tanasova, M.; Sturla, S. J. Chem. Rev. 2012, 112, 3578. doi: 10.1021/cr2001367
18. [18]
  Cross, D. A. E.; Ashton, S. E.; Ghioghiu, S.; Eberlein, C.; Nebhan, C. A.; Spitzler, P. J.; Orme, J. P.; Finlay, M. R. V.; Ward, R. A.; Mellor, M. J.; Hughes, G.; Rahi, A.; Jacobs, V. N.; Brewer, M. R.; Mireille, E.; Sun, J.; Jin, H.; Ballard, P.; Al-Kadhimi, K.; Rowlinson, R.; Klinowska, T.; Richmond, G. H. P.; Cantarini, M.; Kim, D. W.; Ranson, M. R.; Pao, W. Cancer Discovery 2014, 4, 1046.
19. [19]
  Jackson, P. A.; Widen, J. C.; Harki, D. A.; Brummond, K. M. J. Med. Chem. 2017, 60, 839.
20. [20]
  Ward, R. A.; Anderton, M. J.; Ashton, S.; Bethel, P. A.; Box, M.; Butterworth, S. J. Med. Chem. 2013, 56, 7025. doi: 10.1021/jm400822z
21. [21]
  Zhou, W. J.; Ercan, D.; Chen, L.; Yun, C. H.; Li, D. N.; Capelletti, M.; Cortot, A. B.; Chirieac, L.; Iacob, R. E.; Padera, R.; Engen, J. R.; Wong, K. K.; Eck, M. J.; Gray, N. S.; Janne, P. A. Nature 2009, 462, 1070.
22. [22]
  Walter, A. O.; Sjin, R. T.; Haringsma, H. J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z. D.; Wang, Z. G.; Sheets, M.; St Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D. Q.; Nacht, M.; Petter, R. C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; van Dyke, T.; Etter, J.; Weaver, Z.; Pao, W.; Singh, J.; Simmons, A. D.; Harding, T. C.; Allen, A. Cancer Discovery 2013, 3, 1404.
23. [23]
  Campo, E.; Rule, S. Blood 2015, 125, 48.
24. [24]
  Wu, J. J.; Zhang, M. Z.; Liu, D. L. J. Hematol. Oncol. 2016, 9, 21.
25. [25]
  Barf, T.; Covey, T.; Izumi, R.; van der Kar, B.; Gulrajani, M.; van Lith, B.; van Hoek, M.; de Zwart, E.; Mittag, D.; Demont, D.; Verkaik, S.; Krantz, F.; Pearson, P. G.; Ulrich, R.; Kaptein, A. J. Pharmacol. Exp. Ther. 2017, 363, 240. doi: 10.1124/jpet.117.242909
26. [26]
  Byrd, J. C.; Harrington, B.; O'Brien, S.; Jones, J. A.; Schuh, A.; Devereux, S.; Chaves, J.; Wierda, W. G.; Awan, F. T.; Brown, J. R.; Hillmen, P.; Stephens, D. M.; Ghia, P.; Barrientos, J. C.; Pagel, J. M.; Woyach, J.; Johnson, D.; Huang, J.; Wang, X.; Kaptein, A.; Lannutti, B. J.; Covey, T.; Fardis, M.; McGreivy, J.; Hamdy, A.; Rothbaum, W.; Izumi, R.; Diacovo, T. G.; Jojnson, A. J.; Furman, R. R. New. Engl. J. Med. 2016, 374, 323. doi: 10.1056/NEJMoa1509981
27. [27]
  Patel, V.; Balakrishnan, K.; Bibikova, E.; Ayres, M.; Keating, M. J.; Wierda, W. G.; Gandhi, V. Clin. Cancer Res. 2017, 23, 3734.
28. [28]
  Owens, T. D.; Yan, L. Compr. Med. Chem. Ⅲ 2017, 76.
29. [29]
  Meschini, E.; Mora-Vidal, R.; Martin, M. P.; Anscombe, E.; Staunton, D.; Geitmann, M.; Danielson, U. H.; Stanley, W. A.; Wang, L. Z.; Reuillon, T.; Golding, B. T.; Cano, C.; Newell, D. R.; Nobel, M. E. M.; Wedge, S. R.; Endicott, J. A.; Griffin, R. J. Chem. Biol. 2015, 22, 1159.
30. [30]
  Larraufie, M. H.; Yang, W. S.; Jiang, E.; Thomas, A. G.; Slusher, B. S.; Stockwell, B. R. Bioorg. Med. Chem. Lett. 2015, 25, 4787.
31. [31]
  Steinkopf, W. J. Prakt. Chem. 1927, 117, 1.
32. [32]
  Gold, A. M.; Fahrney, D. J. Am. Chem. Soc. 1963, 85, 997.
33. [33]
  Narayanan, A.; Jones, L. H. Chem. Sci. 2015, 6, 2650.
34. [34]
  Dong, J. J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2014, 53, 9430.
35. [35]
  Moss, D. E.; Berlanga, P.; Hagan, M. M.; Sandoval, H. Alzheimer Dis. Assoc. Disord. 1999, 13, 20. doi: 10.1097/00002093-199903000-00003
36. [36]
  Corbett, T. H.; Leopold, W. R.; Dykes, D. J.; Roberts, B. J.; Griswold, D. P.; Schabel, F. M. Cancer Res. 1982, 42, 1707.
37. [37]
  Kumar, A. A.; Mangum, J. H.; Blankenship, D. T.; Freisheim, J. H. J. Biol. Chem. 1981, 256, 8970.
38. [38]
  Baker, B. R.; Wood, W. F. J. Med. Chem. 1969, 12, 214. doi: 10.1021/jm00302a004
39. [39]
  Baker, B. R.; Hurlbut, J. A. J. Med. Chem. 1969, 12, 221.
40. [40]
  Baker, B. R.; Wood, W. F. J. Med. Chem. 1969, 12, 216. doi: 10.1021/jm00302a005
41. [41]
  Karanian, D. A.; Brown, Q. B.; Makriyannis, A.; Kosten, T. A.; Bahr, B. A. J. Neurosci. 2005, 25, 7813.
42. [42]
  Kokotos, G.; Kotsovolou, S.; Constantinou-Kokotou, V.; Wu, G. S.; Olivecrona, G. Bioorg. Med. Chem. Lett. 2000, 10, 2803. doi: 10.1016/S0960-894X(00)00566-7
43. [43]
  Brummond, K. M.; Jackson, P. A.; Widen, J. C.; Harki, D. A. J. Med. Chem. 2017, 60, 839. doi: 10.1021/acs.jmedchem.6b00788
44. [44]
  Gushwa, N. N.; Kang, S. M.; Chen, J.; Taunton, J. J. Am. Chem. Soc. 2012, 134, 20214.
45. [45]
  Potashman, M. H.; Duggan, M. E. J. Med. Chem. 2009, 52, 1231. doi: 10.1021/jm8008597
46. [46]
  Fellenius, E.; Berglindh, T.; Sachs, G.; Olbe, L.; Elander, B.; Sjçstrand, S. E.; Wallmark, B. Nature 1981, 290, 159.
47. [47]
  Gonzμlez-Bello, C. Chem. Med. Chem. 2016, 11, 22. doi: 10.1002/cmdc.v11.1
48. [48]
  Andersson, T.; Rohss, K.; Bredberg, E.; Hassan-Alin, M. Aliment. Pharmacol. Ther. 2001, 15, 1563.
49. [49]
  Baillie, T. A. Angew. Chem., Int. Ed. 2016, 55, 13408.
50. [50]
  Gonzalez-Bello, C. Chem. Med. Chem. 2015, 11, 22.
51. [51]
  Baker, W. L.; White, C. M. Am. J. Cardiovasc. Drugs 2009, 9, 213.
52. [52]
  Wiviott, S. D.; Braunwald, E.; McCabe, C. H.; Montalescot, G.; Ruzyllo, W.; Gottlieb, S.; Neumann, F.; Ardissino, D.; De Servi, S.; Murphy, S. A.; Riesmeyer, J.; Weerakkody, G.; Gibson, C. M.; Antman, E. M. N. Engl. J. Med. 2007, 357, 2001.
53. [53]
  John, J.; Koshy, S. J. Am. Board Fam. Med. 2012, 25, 343.
54. [54]
  Njoroge, F. G.; Chen, X. X.; Shih, N. Y.; Piwinski, J. J. Acc. Chem. Res. 2008, 41, 50.
55. [55]
  Taunton, J.; Serafimova, I. M.; Pufall, M. A.; Krishnan, S.; Duda, K.; Cohen, M. S.; maglathlin, R. L.; McFarlan, J. M.; Miller, R. M.; Frodin, M. Nat. Chem. Biol. 2012, 5, 471.
56. [56]
  Moitessier, N.; De Cesco, S.; Kurian, J.; Dufresne, C.; Mit-termaier, A. K. Eur. J. Med. Chem. 2017, 138, 96.
57. [57]
  Bradshaw, J. W.; McFarland, J. M.; Paavilainen, V. O.; Bisconte, A.; Tam, D.; Phan, V. T.; Romanov, S.; Finkle, D.; Shu, J.; Patel, V.; Ton, T.; Li, X. Y.; Loughhead, D. G.; Nunn, P. A.; Karr, D. E.; Gerritsen, M. E.; Funk, J. O.; Owen, T. D.; Verner, E.; Brameld, K. A.; Hill, R. J.; Goldstein, D. M.; Taunton, J. Nat. Chem. Biol. 2015, 7, 525.
58. [58]
  Liu, Q. S.; Sabnis, Y.; Zhao, Z.; Zhang, T. H.; Buhrlage, S. J.; Jones, L. H.; Gray, N. S. Chem. Biol. 2013, 20, 146. doi: 10.1016/j.chembiol.2012.12.006
1. [1]
  Zhilian Liu , Wengui Wang , Hongxiao Yang , Yu Cui , Shoufeng Wang . Ideological and Political Education Design for the Synthesis of Irinotecan Drug Intermediate 7-Ethyl Camptothecin. University Chemistry, 2024, 39(2): 89-93. doi: 10.3866/PKU.DXHX202306012
2. [2]
  Ziheng Zhuang , Xiao Xu , Kin Shing Chan . Superdrugs for Superbugs. University Chemistry, 2024, 39(9): 128-133. doi: 10.3866/PKU.DXHX202309040
3. [3]
  Peng Zhan . Practice and Reflection in Training Medicinal Chemistry Graduate Students. University Chemistry, 2024, 39(6): 112-121. doi: 10.3866/PKU.DXHX202402022
4. [4]
  Zhibei Qu , Changxin Wang , Lei Li , Jiaze Li , Jun Zhang . Organoid-on-a-Chip for Drug Screening and the Inherent Biochemistry Principles. University Chemistry, 2024, 39(7): 278-286. doi: 10.3866/PKU.DXHX202311039
5. [5]
  Zheqi Wang , Yawen Lin , Shunliu Deng , Huijun Zhang , Jinmei Zhou . Antiviral Strategies: A Brief Review of the Development History of Small Molecule Antiviral Drugs. University Chemistry, 2024, 39(9): 85-93. doi: 10.12461/PKU.DXHX202403108
6. [6]
  Xinyu ZENG , Guhua TANG , Jianming OUYANG . Inhibitory effect of Desmodium styracifolium polysaccharides with different content of carboxyl groups on the growth, aggregation and cell adhesion of calcium oxalate crystals. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1563-1576. doi: 10.11862/CJIC.20230374
7. [7]
  Wenxiu Yang , Jinfeng Zhang , Quanlong Xu , Yun Yang , Lijie Zhang . Bimetallic AuCu Alloy Decorated Covalent Organic Frameworks for Efficient Photocatalytic Hydrogen Production. Acta Physico-Chimica Sinica, 2024, 40(10): 2312014-. doi: 10.3866/PKU.WHXB202312014
8. [8]
  Wendian XIE , Yuehua LONG , Jianyang XIE , Liqun XING , Shixiong SHE , Yan YANG , Zhihao HUANG . Preparation and ion separation performance of oligoether chains enriched covalent organic framework membrane. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1528-1536. doi: 10.11862/CJIC.20240050
9. [9]
  Houzhen Xiao , Mingyu Wang , Yong Liu , Bangsheng Lao , Lingbin Lu , Minghuai Yu . Course Ideological and Political Design of Combustion Heat Measurement Experiment. University Chemistry, 2024, 39(2): 7-13. doi: 10.3866/PKU.DXHX202310011
10. [10]
  Yuan Chun , Lijun Yang , Jinyue Yang , Wei Gao . Ideological and Political Design of BZ Oscillatory Reaction Experiment. University Chemistry, 2024, 39(2): 72-76. doi: 10.3866/PKU.DXHX202308072
11. [11]
  Haiying Jiang , Huilin Guo , Yongliang Cheng , Tongyu Xu , Jiquan Liu , Mingli Peng . Teaching Design of the Nernst Equation Based on the “Flipped Classroom” Method. University Chemistry, 2024, 39(8): 84-90. doi: 10.3866/PKU.DXHX202312091
12. [12]
  Kaihui Huang , Dejun Chen , Xin Zhang , Rongchen Shen , Peng Zhang , Difa Xu , Xin Li . Constructing Covalent Triazine Frameworks/N-Doped Carbon-Coated Cu₂O S-Scheme Heterojunctions for Boosting Photocatalytic Hydrogen Production. Acta Physico-Chimica Sinica, 2024, 40(12): 2407020-. doi: 10.3866/PKU.WHXB202407020
13. [13]
  Fan Wu , Wenchang Tian , Jin Liu , Qiuting Zhang , YanHui Zhong , Zian Lin . Core-Shell Structured Covalent Organic Framework-Coated Silica Microspheres as Mixed-Mode Stationary Phase for High Performance Liquid Chromatography. University Chemistry, 2024, 39(11): 319-326. doi: 10.12461/PKU.DXHX202403031
14. [14]
  Yuanyin Cui , Jinfeng Zhang , Hailiang Chu , Lixian Sun , Kai Dai . Rational Design of Bismuth Based Photocatalysts for Solar Energy Conversion. Acta Physico-Chimica Sinica, 2024, 40(12): 2405016-. doi: 10.3866/PKU.WHXB202405016
15. [15]
  Chunai Dai , Yongsheng Han , Luting Yan , Zhen Li , Yingze Cao . Ideological and Political Design of Solid-liquid Contact Angle Measurement Experiment. University Chemistry, 2024, 39(2): 28-33. doi: 10.3866/PKU.DXHX202306065
16. [16]
  Haiyu Nie , Chenhui Zhang , Fengpei Du . Ideological and Political Design for the Preparation, Characterization and Particle Size Control Experiment of Nanoemulsion. University Chemistry, 2024, 39(2): 41-46. doi: 10.3866/PKU.DXHX202306055
17. [17]
  Yongmei Liu , Lisen Sun , Zhen Huang , Tao Tu . Curriculum-Based Ideological and Political Design for the Experiment of Methanol Oxidation to Formaldehyde Catalyzed by Electrolytic Silver. University Chemistry, 2024, 39(2): 67-71. doi: 10.3866/PKU.DXHX202308020
18. [18]
  Wei Li , Ze Chang , Meihui Yu , Ying Zhang . Curriculum Ideological and Political Design of Piezoelectricity Measurement Experiments of Coordination Compounds. University Chemistry, 2024, 39(2): 77-82. doi: 10.3866/PKU.DXHX202308004
19. [19]
  Ling Liu , Haibin Wang , Genrong Qiang . Curriculum Ideological and Political Design for the Comprehensive Preparation Experiment of Ethyl Benzoate Synthesized from Benzyl Alcohol. University Chemistry, 2024, 39(2): 94-98. doi: 10.3866/PKU.DXHX202304080
20. [20]
  Feng Sha , Xinyan Wu , Ping Hu , Wenqing Zhang , Xiaoyang Luan , Yunfei Ma . Design of Course Ideology and Politics for the Comprehensive Organic Synthesis Experiment of Benzocaine. University Chemistry, 2024, 39(2): 110-115. doi: 10.3866/PKU.DXHX202307082

Get Citation

PDF

XML

Metrics

PDF Downloads(703)
Abstract views(14524)
HTML views(7649)

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