Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Alabi, Shanique; Crews, Craig M.

doi:10.1016/j.jbc.2021.100647

Cited by 136 publications

(124 citation statements)

References 183 publications

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“…These classes include autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs) and antibody-based PROTACs (AbTACs). Collectively, AUTACs and ATTECs have also been categorized as macroautophagy degradation-targeting chimeras (MADTACs) 248 . Like PROTACs, AUTECs and ATTECs focus on intracellular triggering of TPD, while LYTACs and AbTACs trigger intercellular TPD via an extracellular process.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

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1,097

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%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

Self Cite

1,097

996

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“…Further advancement in computational analysis and structure-based optimization methods will likely result in better PROTAC linker design. A more extensive overview of the different linker classes, effects on the multiple aspects of PROTACs properties, and emerging design principles can be found here [ 380 , 381 ].…”

Section: Targeted Protein Degradationmentioning

confidence: 99%

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

LaPlante

Zhang

2021

Cancers

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The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

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“…At present, several challenges remain regarding the development of PROTAC molecules, namely, the rational design of bifunctional molecules and the expansion of the use of various types of E3 ligases other than the currently used ligases (VHL, CRBN, cIAPs, and MDM2) [105]. Moreover, the precise mechanism of action of the degradation machinery in several techniques, including AUTAC, remains unclear [106,107]. A recent report demonstrated that PROTAC-based polyubiquitination could be facilitated by the thyroid hormone receptor-interacting protein 12 (TRIP12), rather than the hijacking of the enzyme by an E3 ligase binder, thus highlighting a role for TRIP12 as an accelerator of PROTAC-directed degradation [108].…”

Section: Discussionmentioning

confidence: 99%

Strategies for Post-Translational Control of Protein Expression and Their Applications

Utsugi

Miyamae

2021

Applied Sciences

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Proteins are fundamental biomolecules of living cells, and their expression levels depend on the balance between the synthesis and degradation. Researchers often aim to control protein expression levels for the investigation of protein function and its relationship with physiological phenomena. The genetic manipulation of the target protein using CRISPR/Cas9, Cre/loxP, tetracyclin system, and RNA interference, are widely used for the regulation of proteins at the DNA, transcriptional, or mRNA level. However, the significant time delay in controlling protein levels is a limitation of these techniques; the knockout or knockdown effects cannot be observed until the previously transcribed and synthesized protein is degraded. Recently, researchers have developed various types of molecular tools for the regulation of protein expression at the post-translational level, which rely on harnessing cellular proteolytic machinery including ubiquitin–proteasome pathway, autophagy-lysosome pathway, and endocytosis. The post-translational control of protein expression using small molecules, antibodies, and light can offer significant advantages regarding speed, tunability, and reversibility. These technologies are expected to be applied to pharmacotherapy and cell therapy, as well as research tools for fundamental biological studies. Here, we review the established and recently developed technologies, provide an update on their applications, and anticipate potential future directions.

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Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Cited by 136 publications

References 183 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Strategies for Post-Translational Control of Protein Expression and Their Applications

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