Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs
Abstract
:1. Introduction
2. Physiological Degradation of Proteins via the Ubiquitin-Proteasome System
3. Peptidic PROTACs
4. IAP-Mediated Small-Molecular Protein Degraders
5. Selective Knockdown of Target Protein
6. Scope of Protein Knockdown
7. IAPs Pan Antagonist-Mediated Protein Knockdown
8. Cereblon and VHL as Components of Small-Molecular PROTACs
9. Conclusions
Funding
Conflicts of Interest
References
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Year | E3 | Target Class | Target Protein | Molecular Weight | Compd No. | Chemical Structure | Efficacy in Cells | Efficacy In Vivo | Ref |
---|---|---|---|---|---|---|---|---|---|
2001 | SCFβTRCP | enzyme | MetAP | 1697 | 1 | - | - | [18] | |
2004 | VHL | Protein-protein interaction | FKBP | 2894 | 2 | 25 μM | - | [19] | |
2008 | MDM2 | Endogenous substrate of E3 | AR | 1210 | 3 | 10 μM | - | [20] | |
2010 | cIAP1 | E3/ binding protein (functionally neutral ligand) | cIAP1/ CRABP-II | 809 | 9 | 1 μM | - | [25] | |
2011 | cIAP1 | Binding protein | CRABP-II | 808 | 11 | 1 μM | - | [26] | |
2011 | cIAP1 | receptor | ER | 764 | 12 | 30 μM | - | [27] | |
2011 | cIAP1 | receptor | AR | 770 | 13 | 30 μM | - | [27] | |
2011 | cIAP1 | receptor | RAR | 917 | 14 | 10 μM | - | [27] | |
2012 | IAPs | E3/ binding protein | cIAP1/ CRABP-II | 1062 | 22 | 100 nM | - | [28] | |
2012 | cIAP1 | receptor | ER | 763 | 15 | 10 μM | - | [29] | |
2015 | cIAP1 | Enzyme/tag | HaloTag- fused proteins | 602 | 17 | 10 μM | - | [30] | |
2015 | Celebron | others | BRD4 | 785 | 36 | 100 nM | 50 mg/kg, IP | [31] | |
2015 | VHL | others | BRD4 | 1002 | 37 | 100 nM | - | [32] | |
2015 | celebron | others | BRD4 | 923 | 38 | 0.3 nM | - | [33] | |
2015 | VHL | enzyme | RIPK | 1060 | 39 | 3 nM | - | [34] | |
2015 | VHL | receptor | ERR | 949 | 40 | 100 nM | 100 mg/kg, ip | [34] | |
2016 | IAPs | Receptor (coactivator binding site) | ER | 3265 | 23 | 20 μM | - | [35] | |
2016 | IAPs | Enzyme/tag | HaloTag- fused protein | 834 | 25 | 1 μM | - | [36] | |
2016 | cIAP1 | enzyme | BCR-ABL | 828 | 18 | 30 μM | - | [37] | |
2017 | IAPs | enzyme (undruggable) | Notch1 | 2989 | 24 | 100 μM | - | [38] | |
2017 | IAPs | E3/ receptor | ER | 1044 | 29 | 3 nM | 10 mg/kg, IP | [39] | |
2017 | IAPs | E3/ enzyme | PDE4 | 1137 | 30 | 1 nM | - | [39] | |
2017 | IAPs | E3/ others | BRD4 | 1056 | 31 | 10 nM | - | [39] | |
2017 | IAPs | E3/ enzyme | BCR-ABL | 1070 | 32 | 10 nM | - | [39] | |
2017 | cIAP1 | aggregation-prone (undruggable) | mHtt | 720 | 19 | 10 μM | - | [40] | |
2017 | cIAP1 | aggregation-prone (undruggable) | mHtt | 662 | 20 | 10 μM | - | [40] | |
2017 | IAPs | enzyme (allosteric site) | BCR-ABL | 1089 | 35 | 30 nM | - | [41] | |
2018 | IAPs | aggregation-prone (undruggable) | mHtt | 974 | 27 | 10 μM | - | [42] | |
2018 | IAPs | E3/ receptor | ER | 1122 | 34 | 10 nM | 30 mg/kg, ip | [43] | |
2018 | IAPs | Tag | HisTag- fused protein | 2116 | 26 | 3 μM | - | [44] | |
2018 | cIAP1 | receptor | AR | 864 | 16 | 10 μM | - | [45] | |
2018 | IAPs | receptor | AR | 984 | 33 | 3 μM | - | [45] | |
2020 | cIAP1 | aggregation-prone (undruggable) | ataxin-3 ataxin-7 atrophin-1 | 19, 20 | (The chemical structures are described above.) | 10 μM | - | [46] |
Compound | R1 | R2 | Aminopeptidase Inhibition pIC50 | cIAP1 Degradation | |
Ala | Arg | ||||
4 | H | H | 7.0 | 7.5 | ++ |
5 | Me | H | 6.9 | 5.7 | +++ |
6 | H | OH | 7.1 | 8.7 | + |
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Ishikawa, M.; Tomoshige, S.; Demizu, Y.; Naito, M. Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs. Pharmaceuticals 2020, 13, 74. https://doi.org/10.3390/ph13040074
Ishikawa M, Tomoshige S, Demizu Y, Naito M. Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs. Pharmaceuticals. 2020; 13(4):74. https://doi.org/10.3390/ph13040074
Chicago/Turabian StyleIshikawa, Minoru, Shusuke Tomoshige, Yosuke Demizu, and Mikihiko Naito. 2020. "Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs" Pharmaceuticals 13, no. 4: 74. https://doi.org/10.3390/ph13040074