Bardoxolone conjugation enables targeted protein degradation of BRD4

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Abstract

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3’s has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.

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Most cited references 43

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Induced protein degradation: an emerging drug discovery paradigm

Ashton C Lai, Craig M Crews (2016)

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.

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Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.

Jing Lu, Yimin Qian, Martha Altieri … (2015)

BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.

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Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

Michael Zengerle, Kwok-Ho Chan, Alessio Ciulli (2015)

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.

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Author and article information

Contributors

Thomas J. Maimone: maimone@berkeley.edu

Daniel K. Nomura: dnomura@berkeley.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 23 September 2020

Publication date PMC-release: 23 September 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 15543

Affiliations

[1 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Department of Chemistry, , University of California, ; Berkeley, CA 94720 USA

[2 ]Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA USA

[3 ]GRID grid.418424.f, ISNI 0000 0004 0439 2056, Novartis Institutes for BioMedical Research, ; Cambridge, MA 02139 USA

[4 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Departments of Molecular and Cell Biology and Nutritional Sciences and Toxicology, , University of California, ; Berkeley, CA 94720 USA

Article

Publisher ID: 72491

DOI: 10.1038/s41598-020-72491-9

PMC ID: 7511954

PubMed ID: 32968148

SO-VID: 24e3a5e7-29b9-434e-a575-d75b96ceec4e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 19 July 2020

Date accepted : 27 August 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01CA240981

Award ID: F31CA239327

Award Recipient : Jessica N. Spradlin

Funded by: FundRef http://dx.doi.org/10.13039/100015311, Novartis Institutes for BioMedical Research;

Funded by: FundRef http://dx.doi.org/10.13039/100014599, Mark Foundation For Cancer Research;

Award ID: ASPIRE Award

Award Recipient : Daniel K. Nomura

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ScienceOpen disciplines: Uncategorized

Keywords: chemical biology,medicinal chemistry,organic chemistry,chemical synthesis,chemical tools,natural products,small molecules

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ScienceOpen disciplines: Uncategorized

Keywords: chemical biology, medicinal chemistry, organic chemistry, chemical synthesis, chemical tools, natural products, small molecules

Bardoxolone conjugation enables targeted protein degradation of BRD4

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Abstract

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Acta Materia Medica

Most cited references 43

Induced protein degradation: an emerging drug discovery paradigm

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

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