Strategy and Design of In Situ Activated Protein Hydrolysis Targeted Chimeras
Source abstract
Abstract
Protein hydrolysis targeted chimeras (PROTACs) represent a different therapeutic approach, particularly relevant for overcoming challenges associated with traditional small molecule inhibitors. These challenges include targeting difficult proteins that are often deemed "undruggable" and addressing issues of acquired resistance. PROTACs employ the body's own E3 ubiquitin ligases to induce the degradation of specific proteins of interest (POIs) through the ubiquitin-proteasome pathway. This process is cyclical, allowing for broad applicability, potent protein degradation, and selective targeting. Despite their effectiveness, PROTACs can inadvertently target and degrade nonspecific proteins, potentially resulting in significant side effects and off-target toxicity. To address this concern, researchers have created stimuli-activated PROTACs that enhance targeted protein degradation while minimizing potential harm to healthy cells. These advanced PROTACs aim to improve the precision of degradation in both time and space. This article reviews the strategies for in situ activated PROTACs, highlighting key compounds and research advancements associated with various mechanisms of action. The insights presented here aim to guide further exploration in the field of activated PROTACs.
Source: openalex_inverted_index · Quality: baseline
Research context
OpenAlex topics: Protein Degradation and Inhibitors · Ubiquitin and proteasome pathways · CAR-T cell therapy research
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Harbin 150001, China
Department of PET-CT/MRI, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Harbin 150001, China
School of Chemistry, Chemical Engineering & Life Science, Wuhan University of Technology, No. 122 Luoshi Road, Wuhan 430070, P. R. China
Faculty of Materials Science, Shenzhen MSU-BIT University
Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemical and Biological Engineering
The Hong Kong University of Science and Technology
Funding
China Postdoctoral Science Foundation · Harbin Medical University Cancer Hospital · National Natural Science Foundation of China · Heilongjiang Postdoctoral Fund · New era Longjiang excellent master?s and doctoral disserations project funding · Harbin Medical University Cancer Hospital Haiyan Foundation · Scientific Research Project of Basic Scientific Research Business Fee ofProvincial Institutions of Higher Education in Heilongjiang Province · Hong Kong scholar project
References (100+)
Show source-provided references
1. 10.1073/pnas.14123079810.1073/pnas.141230798 ↗
2. 10.1016/j.canlet.2023.21606510.1016/j.canlet.2023.216065 ↗
3. 10.1038/s41587-021-01173-210.1038/s41587-021-01173-2 ↗
4. 10.1021/acs.jmedchem.2c0155510.1021/acs.jmedchem.2c01555 ↗
5. 10.1002/bies.20170024710.1002/bies.201700247 ↗
6. 10.1200/JCO.2020.38.15_suppl.350010.1200/JCO.2020.38.15_suppl.3500 ↗
7. 10.1200/JCO.2022.40.6_suppl.01710.1200/JCO.2022.40.6_suppl.017 ↗
8. 10.1038/d41573-021-00052-410.1038/d41573-021-00052-4 ↗
9. 10.1038/s41571-023-00736-310.1038/s41571-023-00736-3 ↗
10. 10.1038/s41573-019-0047-y10.1038/s41573-019-0047-y ↗
11. 10.1038/s41573-021-00371-610.1038/s41573-021-00371-6 ↗
12. 10.1038/s41467-023-44665-210.1038/s41467-023-44665-2 ↗
13. 10.1038/nrd.2016.21110.1038/nrd.2016.211 ↗
14. 10.1016/j.biomaterials.2022.12152310.1016/j.biomaterials.2022.121523 ↗
15. 10.1126/sciadv.abq822510.1126/sciadv.abq8225 ↗
16. 10.1038/nrd89210.1038/nrd892 ↗
17. 10.1038/s41573-021-00245-x10.1038/s41573-021-00245-x ↗
18. 10.1038/nrc.2017.3610.1038/nrc.2017.36 ↗
19. 10.1146/annurev-pharmtox-011613-14002810.1146/annurev-pharmtox-011613-140028 ↗
20. 10.1016/j.ddtec.2019.01.00210.1016/j.ddtec.2019.01.002 ↗
21. 10.1016/j.chembiol.2017.09.01010.1016/j.chembiol.2017.09.010 ↗
22. 10.1126/science.aam734010.1126/science.aam7340 ↗
23. 10.14348/molcells.2018.037210.14348/molcells.2018.0372 ↗
24. 10.1016/0955-0674(95)80031-X10.1016/0955-0674(95)80031-X ↗
25. 10.1074/jbc.R109.01848110.1074/jbc.R109.018481 ↗
26. 10.1016/j.cell.2020.10.03810.1016/j.cell.2020.10.038 ↗
27. 10.1038/nchembio.185810.1038/nchembio.1858 ↗
28. 10.1002/anie.20230804910.1002/anie.202308049 ↗
29. 10.1038/s41467-021-21159-710.1038/s41467-021-21159-7 ↗
30. 10.1016/j.chembiol.2017.09.00910.1016/j.chembiol.2017.09.009 ↗
31. 10.1038/s42003-018-0105-810.1038/s42003-018-0105-8 ↗
32. 10.1073/pnas.152173811310.1073/pnas.1521738113 ↗
33. 10.1002/mco2.29010.1002/mco2.290 ↗
34. 10.1038/nm.437810.1038/nm.4378 ↗
35. 10.1111/bph.1501410.1111/bph.15014 ↗
36. 10.1016/j.pharmthera.2017.02.02710.1016/j.pharmthera.2017.02.027 ↗
37. 10.1016/j.nantod.2024.10231310.1016/j.nantod.2024.102313 ↗
38. 10.1021/acs.nanolett.2c0054010.1021/acs.nanolett.2c00540 ↗
39. 10.1016/j.bioactmat.2021.12.00310.1016/j.bioactmat.2021.12.003 ↗
40. 10.1093/nsr/nwae02810.1093/nsr/nwae028 ↗
41. 10.1039/C0MB00074D10.1039/C0MB00074D ↗
42. 10.1021/acs.jmedchem.6b0191210.1021/acs.jmedchem.6b01912 ↗
43. 10.1073/pnas.180366211510.1073/pnas.1803662115 ↗
44. 10.1021/ja310323y10.1021/ja310323y ↗
45. 10.1002/chem.20140464910.1002/chem.201404649 ↗
46. 10.1021/acscentsci.9b0071310.1021/acscentsci.9b00713 ↗
47. 10.1021/acs.jmedchem.9b0205810.1021/acs.jmedchem.9b02058 ↗
48. 10.1021/jacs.1c0045110.1021/jacs.1c00451 ↗
49. 10.1021/acschembio.0c0028510.1021/acschembio.0c00285 ↗
50. 10.1126/science.aab143310.1126/science.aab1433 ↗
51. 10.1038/nature1352710.1038/nature13527 ↗
52. 10.1016/j.ejmech.2018.03.07110.1016/j.ejmech.2018.03.071 ↗
53. 10.1126/sciadv.aay515410.1126/sciadv.aay5154 ↗
54. 10.1021/jacs.9b0642210.1021/jacs.9b06422 ↗
55. 10.1021/acscentsci.6b0028010.1021/acscentsci.6b00280 ↗
56. 10.1126/sciadv.abq221610.1126/sciadv.abq2216 ↗
57. 10.1002/anie.20230682410.1002/anie.202306824 ↗
58. 10.1039/C7CS00521K10.1039/C7CS00521K ↗
59. 10.1038/nrd.2018.4610.1038/nrd.2018.46 ↗
60. 10.1002/advs.20200236510.1002/advs.202002365 ↗
61. 10.1016/j.addr.2017.06.01310.1016/j.addr.2017.06.013 ↗
62. 10.1038/nn.409110.1038/nn.4091 ↗
63. 10.1039/D0CC00523A10.1039/D0CC00523A ↗
64. 10.1016/j.jconrel.2019.02.00610.1016/j.jconrel.2019.02.006 ↗
65. 10.1126/sciadv.aay506410.1126/sciadv.aay5064 ↗
66. 10.1016/j.ejmech.2021.11360810.1016/j.ejmech.2021.113608 ↗
67. 10.1002/anie.20160193110.1002/anie.201601931 ↗
68. 10.1021/acs.chemrev.8b0003710.1021/acs.chemrev.8b00037 ↗
69. 10.1146/annurev-neuro-061010-11381710.1146/annurev-neuro-061010-113817 ↗
70. 10.1097/ICU.000000000000014010.1097/ICU.0000000000000140 ↗
71. 10.1242/dev.17506710.1242/dev.175067 ↗
72. 10.1007/s40291-022-00586-210.1007/s40291-022-00586-2 ↗
73. 10.1016/j.scib.2023.04.02810.1016/j.scib.2023.04.028 ↗
74. 10.1021/jacs.9b1271810.1021/jacs.9b12718 ↗
75. 10.1038/nature0076710.1038/nature00767 ↗
76. 10.1126/science.107344010.1126/science.1073440 ↗
77. 10.1055/s-2006-94242410.1055/s-2006-942424 ↗
78. 10.1021/ja100710j10.1021/ja100710j ↗
79. 10.1039/C8CS00001H10.1039/C8CS00001H ↗
80. 10.1021/jacs.3c0410910.1021/jacs.3c04109 ↗
81. 10.1016/j.addr.2010.04.00910.1016/j.addr.2010.04.009 ↗
82. 10.1038/s41571-021-00579-w10.1038/s41571-021-00579-w ↗
83. 10.1021/jacs.2c1017710.1021/jacs.2c10177 ↗
84. 10.1038/nrc70410.1038/nrc704 ↗
85. 10.1038/nrc225510.1038/nrc2255 ↗
86. 10.1039/C5CC03824C10.1039/C5CC03824C ↗
87. 10.1016/j.canlet.2014.01.03210.1016/j.canlet.2014.01.032 ↗
88. 10.1021/acs.jmedchem.1c0222110.1021/acs.jmedchem.1c02221 ↗
89. 10.1039/D1CC05715D10.1039/D1CC05715D ↗
90. Szatrowski T. P. · Cancer Res. · 1991 · 51 · 794
91. 10.1042/BST2019004910.1042/BST20190049 ↗
92. 10.1038/nrd133010.1038/nrd1330 ↗
93. 10.1039/D2CC03367D10.1039/D2CC03367D ↗
94. 10.1021/acs.jmedchem.1c0090110.1021/acs.jmedchem.1c00901 ↗
95. 10.1038/nrm380110.1038/nrm3801 ↗
96. 10.1002/anie.20210734710.1002/anie.202107347 ↗
97. 10.1124/mol.109.05594710.1124/mol.109.055947 ↗
98. 10.1038/s41467-017-01565-610.1038/s41467-017-01565-6 ↗
99. 10.1021/jacs.9b0866910.1021/jacs.9b08669 ↗
100. 10.1128/AEM.01758-2110.1128/AEM.01758-21 ↗