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Article ; Online: Advances and opportunities in targeted protein degradation.

Nomura, Daniel K / Dey, Mishtu

Cell chemical biology

2021 Volume 28, Issue 7, Page(s) 887–888

MeSH term(s)	Humans ; Proteolysis ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2021-07-16
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2021.06.011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Virtual Issue on the Work of John Casida.

Nomura, Daniel K

Chemical research in toxicology

2018 Volume 31, Issue 8, Page(s) 637–638

MeSH term(s)	California ; History, 20th Century ; History, 21st Century ; Toxicology
Language	English
Publishing date	2018-08-06
Publishing country	United States
Document type	Biography ; Editorial ; Historical Article ; Introductory Journal Article
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.8b00195
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Article ; Online: Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation.

Hong, Seong Ho / Divakaran, Anand / Osa, Akane / Huang, Oscar W / Wertz, Ingrid E / Nomura, Daniel K

ACS chemical biology

2024 Volume 19, Issue 2, Page(s) 442–450

Abstract: Targeted protein degradation with proteolysis targeting chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Most PROTACs have exploited ... ...

Abstract	Targeted protein degradation with proteolysis targeting chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Most PROTACs have exploited substrate receptors of Cullin-RING E3 ubiquitin ligases such as cereblon and VHL. Whether core, shared, and essential components of the Cullin-RING E3 ubiquitin ligase complex can be used for PROTAC applications remains less explored. Here, we discovered a cysteine-reactive covalent recruiter EN884 against the SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex. We further showed that this recruiter can be used in PROTAC applications to degrade neo-substrate proteins such as BRD4 and the androgen receptor in a SKP1- and proteasome-dependent manner. Our studies demonstrate that core and essential adapter proteins within the Cullin-RING E3 ubiquitin ligase complex can be exploited for targeted protein degradation applications and that covalent chemoproteomic strategies can enable recruiter discovery against these targets.
MeSH term(s)	Ubiquitin-Protein Ligases/metabolism ; Cullin Proteins/metabolism ; Proteolysis ; Proteasome Endopeptidase Complex/metabolism ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; S-Phase Kinase-Associated Proteins/metabolism ; Adaptor Proteins, Signal Transducing/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Cullin Proteins ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Nuclear Proteins ; Transcription Factors ; S-Phase Kinase-Associated Proteins ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00642
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1.

Meyers, Margot / Cismoski, Sabine / Panidapu, Anoohya / Chie-Leon, Barbara / Nomura, Daniel K

ACS chemical biology

2024 Volume 19, Issue 1, Page(s) 58–68

Abstract: Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ... ...

Abstract	Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4 adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.
MeSH term(s)	Proteolysis ; Cullin Proteins/metabolism ; Transcription Factors/metabolism ; Nuclear Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Adaptor Proteins, Signal Transducing/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Isoforms/metabolism
Chemical Substances	Cullin Proteins ; Transcription Factors ; Nuclear Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Adaptor Proteins, Signal Transducing ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Protein Isoforms
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00487
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Covalent 14-3-3 Molecular Glues and Heterobifunctional Molecules Against Nuclear Transcription Factors and Regulators.

Shao, Qian / Duong, Tuong Nghi / Park, Inji / Nomura, Daniel K

bioRxiv : the preprint server for biology

2023

Abstract: 14-3-3 proteins have the unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that 14-3-3 interactions with specific phosphorylated substrate proteins ... ...

Abstract	14-3-3 proteins have the unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that 14-3-3 interactions with specific phosphorylated substrate proteins can be enhanced through small-molecule natural product or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates as well as potential neo-substrates to sequester and inhibit their function has remained elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has a cysteine C38 at the substrate binding interface near sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screened a fully synthetic cysteine-reactive covalent ligand library to identify molecular glues that enhance interaction of 14-3-3σ with not only druggable transcription factors such as estrogen receptor (ERα), but also challenging oncogenic transcription factors such as YAP and TAZ that are part of the Hippo transducer pathway. We identified a hit EN171 that covalently targets 14-3-3 to enhance 14-3-3 interactions with ERα, YAP, and TAZ leading to impaired estrogen receptor and Hippo pathway transcriptional activity. We further demonstrate that EN171 could not only be used as a molecular glue to enhance native protein interactions, but also could be used as a covalent 14-3-3 recruiter in heterobifunctional molecules to sequester nuclear neo-substrates such as BRD4 into the cytosol. Overall, our study reveals a covalent ligand that acts as a novel 14-3-3 molecular glue for challenging transcription factors such as YAP and TAZ and also demonstrates that these glues can be potentially utilized in heterobifunctional molecules to sequester nuclear neo-substrates out of the nucleus and into the cytosol to enable targeted protein localization.
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.06.565850
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Article ; Online: N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics.

Koo, Tin-Yan / Lai, Hinyuk / Nomura, Daniel K / Chung, Clive Yik-Sham

Nature communications

2023 Volume 14, Issue 1, Page(s) 3564

Abstract: Cysteine has been exploited as the binding site of covalent drugs. Its high sensitivity to oxidation is also important for regulating cellular processes. To identify new ligandable cysteines which can be hotspots for therapy and to better study cysteine ... ...

Abstract	Cysteine has been exploited as the binding site of covalent drugs. Its high sensitivity to oxidation is also important for regulating cellular processes. To identify new ligandable cysteines which can be hotspots for therapy and to better study cysteine oxidations, we develop cysteine-reactive probes, N-acryloylindole-alkynes (NAIAs), which have superior cysteine reactivity owing to delocalization of π electrons of the acrylamide warhead over the whole indole scaffold. This allows NAIAs to probe functional cysteines more effectively than conventional iodoacetamide-alkyne, and to image oxidized thiols by confocal fluorescence microscopy. In mass spectrometry experiments, NAIAs successfully capture new oxidized cysteines, as well as a new pool of ligandable cysteines and proteins. Competitive activity-based protein profiling experiments further demonstrate the ability of NAIA to discover lead compounds targeting these cysteines and proteins. We show the development of NAIAs with activated acrylamide for advancing proteome-wide profiling and imaging ligandable cysteines and oxidized thiols.
MeSH term(s)	Cysteine/metabolism ; Sulfhydryl Compounds/chemistry ; Alkynes/chemistry ; Proteins/chemistry ; Acrylamides
Chemical Substances	Cysteine (K848JZ4886) ; Sulfhydryl Compounds ; Alkynes ; Proteins ; Acrylamides
Language	English
Publishing date	2023-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39268-w
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Article ; Online: Advances in covalent drug discovery.

Boike, Lydia / Henning, Nathaniel J / Nomura, Daniel K

Nature reviews. Drug discovery

2022 Volume 21, Issue 12, Page(s) 881–898

Abstract: Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable ... ...

Abstract	Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through 'electrophile-first' approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field.
MeSH term(s)	Humans ; Drug Discovery/methods ; Ligands ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins p21(ras)/metabolism ; SARS-CoV-2 ; Structure-Activity Relationship ; COVID-19 Drug Treatment
Chemical Substances	Ligands ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; BTK protein, human (EC 2.7.10.2) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2022-08-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-022-00542-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 5564: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 334: Show issues
Zs.MG 63: Show issues

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Article: Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation.

Hong, Seong Ho / Osa, Akane / Huang, Oscar W / Wertz, Ingrid E / Nomura, Daniel K

bioRxiv : the preprint server for biology

2023

Abstract: Targeted protein degradation with Proteolysis Targeting Chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Most PROTACs have exploited ... ...

Abstract	Targeted protein degradation with Proteolysis Targeting Chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Most PROTACs have exploited substrate receptors of Cullin-RING E3 ubiquitin ligases such as cereblon and VHL. Whether core, shared, and essential components of the Cullin-RING E3 ubiquitin ligase complex can be used for PROTAC applications remains less explored. Here, we discovered a cysteine-reactive covalent recruiter EN884 against the SKP1 adapter protein of the SKP1-CUL1-F-box containing SCF complex. We further showed that this recruiter can be used in PROTAC applications to degrade neo-substrate proteins such as BRD4 and the androgen receptor in a SKP1- and proteasome-dependent manner. Our studies demonstrate that core and essential adapter proteins within the Cullin-RING E3 ubiquitin ligase complex can be exploited for targeted protein degradation applications and that covalent chemoproteomic strategies can enable recruiter discovery against these targets.
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.20.563371
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1.

Meyers, Margot / Cismoski, Sabine / Panidapu, Anoohya / Chie-Leon, Barbara / Nomura, Daniel K

bioRxiv : the preprint server for biology

2023

Abstract: Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ... ...

Abstract	Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4A adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.
Language	English
Publishing date	2023-08-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.11.553046
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Article ; Online: Ligandability of E3 Ligases for Targeted Protein Degradation Applications.

Belcher, Bridget P / Ward, Carl C / Nomura, Daniel K

Biochemistry

2021 Volume 62, Issue 3, Page(s) 588–600

Abstract: Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ ... ...

Abstract	Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ heterobifunctional or monovalent small molecules, respectively, to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. Whereas TPD is an attractive therapeutic strategy for expanding the druggable proteome, only a relatively small number of E3 ligases out of the >600 E3 ligases encoded by the human genome have been exploited by small molecules for TPD applications. Here we review the existing E3 ligases that have thus far been successfully exploited for TPD and discuss chemoproteomics-enabled covalent screening strategies for discovering new E3 ligase recruiters. We also provide a chemoproteomic map of reactive cysteines within hundreds of E3 ligases that may represent potential ligandable sites that can be pharmacologically interrogated to uncover additional E3 ligase recruiters.
MeSH term(s)	Humans ; Ubiquitin-Protein Ligases/metabolism ; Proteolysis ; Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitination
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteins ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2021-09-02
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.1c00464
Database	MEDical Literature Analysis and Retrieval System OnLINE

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