Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras

Samarasinghe, Kusal T. G.; Jaime‐Figueroa, Saul; Burgess, Michael; Nalawansha, Dhanusha A.; Dai, Katherine; Hu, Zhifeng; Bebenek, Adrian M.; Holley, Scott A.; Crews, Craig M.

doi:10.1016/j.chembiol.2021.03.011

Cited by 119 publications

(105 citation statements)

References 71 publications

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“…TRAFTACs consist of a HaloPROTAC that bridges an E3 ligase and a dCas9–HT7 fusion protein, then binds a bifunctional dsDNA–CRISPR-RNA to form a transcription factor-recruiting complex. The TRAFTAC system has been used to degrade NF-κB and brachyury (T-box transcription factor T; TBXT) in human cell lines in a UPS-dependent manner that was specific to the dsDNA sequence and E3 ligase 43 .…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

“…The basic science behind TPD has grown exponentially and matured substantially in the past few years (for example, as reviewed in reFs [42][43][44] ). In our opinion, the next milestones in this 'new era' of TPD will focus on four clinical translation inflexion points, namely, defining and clinically demonstrating the target classes best served by degradation over inhibition; expanding the scope of E3 ubiquitin ligases employed clinically in a Box 1 | strategies for discovery of molecular glues Rational degrader discovery using the modular proteolysis-targeting chimera (PROTAC) strategy (Fig.…”

Section: Clinical Proof Of Concept For Protacsmentioning

confidence: 99%

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PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

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1,530

996

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Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

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Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

Section: Clinical Proof Of Concept For Protacsmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

Self Cite

1,530

996

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“…In 2021, TRAnscription Factor Targeting Chimeras (TRAFTACs) technology was developed. The TRAFTAC system is composed of a HaloTag-fused dCas9 protein and a chimeric oligonucleotide that can bind transcription factor of interest (TOI) and dCas9 simultaneously [101]. This system labels the TOI with ubiquitin which then degrades the TOI by proteasomal machinery.…”

Section: Potential Pharmacological Inhibitors Of Snai1mentioning

confidence: 99%

Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis

Dong

2021

IJMS

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SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and post-translational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis.

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“…These new chimeric structures include a small, structurally modified oligoribonucleotide (iso-sequential to the native RNA-binding element of the RBP), which serves the function of docking to the protein RNA-binding site, and an E3-recruiting peptide, derived from the HIF-1a protein, which labels the RBP for proteasomal degradation. The Crews lab reported an oligo-PROTAC-based strategy for targeted transcription-factor degradation, TRAnscription Factor Targeting Chimeras (TRAFTACs) [ 229 ]. TRAFTACs consist of a chimeric oligonucleotide that simultaneously binds to the transcription factor of interest (TOI) and to HaloTag fused dCas9 protein.…”

Section: Emerging Rna-based Technologiesmentioning

confidence: 99%

Innovative developments and emerging technologies in RNA therapeutics

et al. 2022

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RNA-based therapeutics are emerging as a powerful platform for the treatment of multiple diseases. Currently, the two main categories of nucleic acid therapeutics, antisense oligonucleotides and small interfering RNAs (siRNAs), achieve their therapeutic effect through either gene silencing, splicing modulation or microRNA binding, giving rise to versatile options to target pathogenic gene expression patterns. Moreover, ongoing research seeks to expand the scope of RNA-based drugs to include more complex nucleic acid templates, such as messenger RNA, as exemplified by the first approved mRNA-based vaccine in 2020. The increasing number of approved sequences and ongoing clinical trials has attracted considerable interest in the chemical development of oligonucleotides and nucleic acids as drugs, especially since the FDA approval of the first siRNA drug in 2018. As a result, a variety of innovative approaches is emerging, highlighting the potential of RNA as one of the most prominent therapeutic tools in the drug design and development pipeline. This review seeks to provide a comprehensive summary of current efforts in academia and industry aimed at fully realizing the potential of RNA-based therapeutics. Towards this, we introduce established and emerging RNA-based technologies, with a focus on their potential as biosensors and therapeutics. We then describe their mechanisms of action and their application in different disease contexts, along with the strengths and limitations of each strategy. Since the nucleic acid toolbox is rapidly expanding, we also introduce RNA minimal architectures, RNA/protein cleavers and viral RNA as promising modalities for new therapeutics and discuss future directions for the field.

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Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras

Abstract: Highlights d TRAFTACs are heterobifunctional chimeric oligos d Transcription factors are recruited to the double-stranded DNA of the chimeric TRAFTACs d TRAFTACs are generalizable d Brachyury-TRAFTAC induces no tail phenotype in zebrafish embryos

Cited by 119 publications

References 71 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis

Innovative developments and emerging technologies in RNA therapeutics

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