An E3 ligase guide to the galaxy of small-molecule-induced protein degradation

Jevtić, Predrag; Haakonsen, Diane L.; Rapé, Michael

doi:10.1016/j.chembiol.2021.04.002

Cited by 80 publications

(57 citation statements)

References 194 publications

(174 reference statements)

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“…b | Table showing representative E3 ligase examples from different mechanistic classes of E3 ligase, highlighting their various (but not exhaustive) attributes to be considered for proteolysis-targeting chimera (PROTAC) development, including tumour and tissue enrichment, tumour dependence (CERES/DepMap profile) and mechanistic understanding of ubiquitin ligation onto their substrates. The E3 examples were chosen for each E3 class from multiple E3-centric review articles 80 , 99 , 139 , 228 , 229 to highlight various characteristics and the expansive choice in ligase selection for novel PROTACs. One article is referenced for each E3, but there is considerable overlap between the content of the cited references.…”

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

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%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,530

996

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“…We suggest that highly potent and promiscuous effectors identified in our screen (such as FBXL12, FBXL15, KLHDC2, or KBTBD7) may provide a more robust platform for the development of novel targeted protein degradation therapeutics, as these effectors are likely to be less sensitive to linker chemistries, target localization, and other parameters. On the other hand, picking more specific effectors that are expressed in a limited number of tissues (Jevtić et al, 2021) could alleviate potential off-target effects of next generation PROTACs and DUBTACs.…”

Section: Inherent Differences In E3 Ligase and Dub Efficacymentioning

confidence: 99%

Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers

Poirson

Dhillon

Cho

et al. 2022

Preprint

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Targeted protein degradation and stabilization are promising therapeutic modalities due to their potency and versatility. However, only few E3 ligases and deubiquitinases have been harnessed for this purpose. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation. Here, we used a proteome-scale platform to identify hundreds of human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. This allowed us to comprehensively compare the activities of human E3s and deubiquitinases, characterize non-canonical protein degraders and stabilizers, and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3s CBRN and VHL. Our study provides a functional catalogue of effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for discovery of novel proximity-dependent protein modulators.

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“…Proteasome target proteins are ubiquitylated by E3 ubiquitin ligases which transfer the ubiquityl group from E2 ligase to the target protein. There are ∼600 E3 ligases encoded in the mammalian genome ( 140 ). The ubiquitin ligases, which are not proteases but included in ubiquitin-proteasome system-mediated protein degradation, indispensable for mammalian reproduction are listed in Table 2 .…”

Section: Multicellular Organisms Ii: Vertebratesmentioning

confidence: 99%

Proteolysis in Reproduction: Lessons From Gene-Modified Organism Studies

Kiyozumi

Ikawa

2022

Front. Endocrinol.

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The physiological roles of proteolysis are not limited to degrading unnecessary proteins. Proteolysis plays pivotal roles in various biological processes through cleaving peptide bonds to activate and inactivate proteins including enzymes, transcription factors, and receptors. As a wide range of cellular processes is regulated by proteolysis, abnormalities or dysregulation of such proteolytic processes therefore often cause diseases. Recent genetic studies have clarified the inclusion of proteases and protease inhibitors in various reproductive processes such as development of gonads, generation and activation of gametes, and physical interaction between gametes in various species including yeast, animals, and plants. Such studies not only clarify proteolysis-related factors but the biological processes regulated by proteolysis for successful reproduction. Here the physiological roles of proteases and proteolysis in reproduction will be reviewed based on findings using gene-modified organisms.

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An E3 ligase guide to the galaxy of small-molecule-induced protein degradation

Cited by 80 publications

References 194 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers

Proteolysis in Reproduction: Lessons From Gene-Modified Organism Studies

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