Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.
Journal
Journal of the American Chemical Society
ISSN: 1520-5126
Titre abrégé: J Am Chem Soc
Pays: United States
ID NLM: 7503056
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
pubmed:
15
9
2021
medline:
19
2
2022
entrez:
14
9
2021
Statut:
ppublish
Résumé
Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
Identifiants
pubmed: 34520194
doi: 10.1021/jacs.1c04841
pmc: PMC8480205
mid: NIHMS1741244
doi:
Substances chimiques
Antineoplastic Agents
0
KEAP1 protein, human
0
Kelch-Like ECH-Associated Protein 1
0
MS83 compound
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15073-15083Subventions
Organisme : NCI NIH HHS
ID : R01 CA218600
Pays : United States
Organisme : NIH HHS
ID : S10 OD028504
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260666
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM122749
Pays : United States
Organisme : NIH HHS
ID : S10 OD025132
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230854
Pays : United States
Références
Mol Cell Biol. 2004 Dec;24(24):10941-53
pubmed: 15572695
Nat Struct Mol Biol. 2020 Apr;27(4):333-341
pubmed: 32203489
Nat Rev Drug Discov. 2019 Dec;18(12):949-963
pubmed: 31666732
J Med Chem. 2016 Apr 28;59(8):3991-4006
pubmed: 27031670
Eur J Med Chem. 2018 Feb 25;146:251-259
pubmed: 29407955
Nat Chem Biol. 2015 Aug;11(8):611-7
pubmed: 26075522
PLoS One. 2014 Jun 04;9(6):e98896
pubmed: 24896564
Nat Chem Biol. 2020 Feb;16(2):214-222
pubmed: 31819273
EMBO J. 2013 Aug 28;32(17):2307-20
pubmed: 23912815
Science. 2015 Jun 19;348(6241):1376-81
pubmed: 25999370
SLAS Discov. 2021 Apr;26(4):484-502
pubmed: 33143537
Cell. 2011 Sep 16;146(6):904-17
pubmed: 21889194
J Med Chem. 2020 Sep 10;63(17):9965-9976
pubmed: 32787104
Mol Cell. 2020 Jun 18;78(6):1114-1132.e10
pubmed: 32446320
Cancer Res. 2017 May 1;77(9):2476-2487
pubmed: 28209615
J Med Chem. 2019 May 9;62(9):4683-4702
pubmed: 30973731
J Med Chem. 2018 Sep 27;61(18):8088-8103
pubmed: 29750408
Nat Rev Cancer. 2021 Oct;21(10):638-654
pubmed: 34131295
Bioorg Med Chem Lett. 1998 Oct 6;8(19):2711-4
pubmed: 9873608
Drug Discov Today Technol. 2019 Apr;31:15-27
pubmed: 31200855
Mol Cell Biol. 2006 Apr;26(8):2887-900
pubmed: 16581765
Cancer Res. 2019 Jan 1;79(1):251-262
pubmed: 30385614
Sci Rep. 2020 Sep 23;10(1):15543
pubmed: 32968148
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
PLoS One. 2011;6(7):e22862
pubmed: 21818401
Med Chem Res. 2020 May;29(5):846-867
pubmed: 32390710
Ther Adv Hematol. 2015 Jun;6(3):128-41
pubmed: 26137204
Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5
pubmed: 29129718
Mol Cancer. 2018 Nov 22;17(1):164
pubmed: 30466442