A PROTAC targets splicing factor 3B1

Gama-Brambila, Rodrigo A.; Chen, Jie; Zhou, Jun; Tascher, Georg; Münch, Christian; Cheng, Xinlai

doi:10.1016/j.chembiol.2021.04.018

Cited by 20 publications

(13 citation statements)

References 72 publications

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“…ATP hydrolysis is required for ubiquitination of targeted proteins and 26S proteasome–mediated protein degradation ( Peth et al, 2013 ). We adapted our recently developed in vitro ubiquitination assay to investigate chemically induced target protein degradation in vitro by determination of ATP consumption and immunoblotting ( Gama-Brambila et al, 2021a , 2021b ). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

Zhou

Dabiri

Gama-Brambila

et al. 2021

Journal of Cell Biology

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Transforming growth factor β (TGF-β) signaling plays a fundamental role in metazoan development and tissue homeostasis. However, the molecular mechanisms concerning the ubiquitin-related dynamic regulation of TGF-β signaling are not thoroughly understood. Using a combination of proteomics and an siRNA screen, we identify pVHL as an E3 ligase for SMAD3 ubiquitination. We show that pVHL directly interacts with conserved lysine and proline residues in the MH2 domain of SMAD3, triggering degradation. As a result, the level of pVHL expression negatively correlates with the expression and activity of SMAD3 in cells, Drosophila wing, and patient tissues. In Drosophila, loss of pVHL leads to the up-regulation of TGF-β targets visible in a downward wing blade phenotype, which is rescued by inhibition of SMAD activity. Drosophila pVHL expression exhibited ectopic veinlets and reduced wing growth in a similar manner as upon loss of TGF-β/SMAD signaling. Thus, our study demonstrates a conserved role of pVHL in the regulation of TGF-β/SMAD3 signaling in human cells and Drosophila wing development.

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Section: Resultsmentioning

confidence: 99%

“…As described before ( Gama-Brambila et al, 2021a , 2021b ) pVHL KD cells were transfected with FLAG-SMAD3 variants and freshly lysed with immunoprecipitation buffer before use. The HA-pVHL variants were individually expressed in HeLa cells and freshly isolated using FLAG immunoprecipitation kit according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

Zhou

Dabiri

Gama-Brambila

et al. 2021

Journal of Cell Biology

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“…Gama-Brambila et al recently reported the development of transcription factor-targeting chimeras (TRAFTACs) as a suitable strategy for targeted transcription factor degradation. 44 Huang et al developed another strategy to induce the degradation of transcription factors using oligonucleotidebased PROTACs (O'PROTACs). 54 Whether TRAFTAC or O'PROTAC is a better strategy to degrade FOXM1 may be of In vitro plasma half-life.…”

Section: ■ Conclusion and Discussionmentioning

confidence: 99%

“…In contrast to traditional small-molecule inhibitors that act in occupancy-driven modes of action, PROTACs seem to exert protein degradation catalytically, requiring only transient binding to POI, and can show biological effects even at substoichiometric quantities . This relatively new strategy offers a unique opportunity for targeting noncatalytic proteins such as transcription factors, splicing factors, and structural scaffolds. − Nevertheless, despite tremendous progress achieved over the past decade, most PROTACs target conventional proteins representing a small part of the vast group of transcription factors for which there is some data on ligand-binding sites . The use of PROTACs to degrade those “undruggable” DNA-binding proteins is still gaining momentum .…”

Section: Introductionmentioning

confidence: 99%

Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation

et al. 2021

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The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein− protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.

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“…68 ) by fusing thalidomide to O4I. 417 They found the degrader 215 ( PROTAC-O4I2 ) selectively induced the degradation of SF3B1 and induced cellular apoptosis in a CRBN-dependent manner. In a Drosophila intestinal tumor model, the degrader 215 ( PROTAC-O4I2 ) increased survival by interference with the maintenance and proliferation of stem cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

115

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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A PROTAC targets splicing factor 3B1

Cited by 20 publications

References 72 publications

pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

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