Light-Induced Protein Degradation with Photocaged PROTACs DOI
Gang Xue, Kun Wang, Danli Zhou

et al.

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(46), P. 18370 - 18374

Published: Sept. 30, 2019

Induction of protein degradation is emerging as a powerful strategy to modulate functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used degrade range diverse proteins in vitro vivo. Here we present type photo-caged PROTACs (pc-PROTACs) induce activity with light. Photo-removable blocking groups were added degrader Brd4, the resulting molecule pc-PROTAC1 showed potent live cells only after light irradiation. Furthermore, this efficiently degraded Brd4 induced expected phenotypic changes zebrafish. Additionally, approach was successfully applied construct pc-PROTAC3 BTK. Thus, general established augment chemists' toolbox study disease-relevant targets.

Language: Английский

PROTAC targeted protein degraders: the past is prologue DOI Open Access
Miklós Békés, David R. Langley, Craig M. Crews

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(3), P. 181 - 200

Published: Jan. 18, 2022

Language: Английский

Citations

1856
Kinase inhibitors: the road ahead DOI
Fleur M. Ferguson, Nathanael S. Gray

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(5), P. 353 - 377

Published: March 16, 2018

Language: Английский

Citations

892
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery DOI Creative Commons
George M. Burslem, Craig M. Crews

Cell, Journal Year: 2020, Volume and Issue: 181(1), P. 102 - 114

Published: Jan. 16, 2020

Language: Английский

Citations

776
Targeted protein degradation: expanding the toolbox DOI
Matthieu Schapira, Matthew F. Calabrese, Alex N. Bullock

et al.

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(12), P. 949 - 963

Published: Oct. 30, 2019

Language: Английский

Citations

718
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future DOI Creative Commons

Mariell Pettersson,

Craig M. Crews

Drug Discovery Today Technologies, Journal Year: 2019, Volume and Issue: 31, P. 15 - 27

Published: Feb. 13, 2019

The majority of currently used therapeutics are small molecule-based and utilize occupancy-driven pharmacology as the mode action (MOA), in which protein function is modulated via temporary inhibition. New modalities that operate using alternative MOAs essential for tapping into "undruggable" proteome. PROteolysis Targeting Chimera (PROTAC) technology provides an attractive new approach utilizes event-driven MOA. Small heterobifunctional PROTACs modulate target levels by hijacking ubiquitin-proteasome system to induce degradation target. Here, we address important milestones development PROTAC technology, well emphasize key findings from this previous year highlight future directions promising drug discovery modality.

Language: Английский

Citations

601
Plasticity in binding confers selectivity in ligand-induced protein degradation DOI
Radosław P. Nowak, Stephen L. DeAngelo, Dennis L. Buckley

et al.

Nature Chemical Biology, Journal Year: 2018, Volume and Issue: 14(7), P. 706 - 714

Published: June 8, 2018

Language: Английский

Citations

522
PROTACs: great opportunities for academia and industry DOI Creative Commons
Xiuyun Sun, Hongying Gao, Yiqing Yang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 24, 2019

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic limited number drug targets, which presently only 20-25% all protein targets that currently being studied. Moreover, focus current explorations their enzymatic functions, ignores functions from scaffold moiety. As promising appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both academia industry for finding available approaches to solve above problems. PROTACs regulate function by degrading target proteins instead inhibiting them, providing more sensitivity drug-resistant greater chance affect nonenzymatic functions. been proven show better selectivity compared classic inhibitors. can be described as chemical knockdown approach with rapidity reversibility, presents new different biology other gene editing tools avoiding misinterpretations arise potential genetic compensation and/or spontaneous mutations. PRTOACs widely explored throughout world outperformed not cancer diseases, but also immune disorders, viral infections neurodegenerative diseases. present very powerful crossing hurdles discovery tool development biology, efforts needed gain get deeper insight into efficacy safety clinic. More binders E3 ligases applicable developing waiting exploration.

Language: Английский

Citations

513
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity DOI
Sajid Khan, Xuan Zhang, Dongwen Lv

et al.

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(12), P. 1938 - 1947

Published: Dec. 1, 2019

Language: Английский

Citations

500
Targeted protein degradation: elements of PROTAC design DOI
Stacey-Lynn Paiva, Craig M. Crews

Current Opinion in Chemical Biology, Journal Year: 2019, Volume and Issue: 50, P. 111 - 119

Published: April 17, 2019

Language: Английский

Citations

481
Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase DOI Creative Commons
Blake E. Smith, Stephen L. Wang, Saul Jaime‐Figueroa

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 4, 2019

Abstract PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related families remain elusive. Here, we generate isoform-selective p38 MAPK family using single warhead (foretinib) and recruited (von Hippel-Lindau). Based on their distinct linker attachments lengths, these two differentially VHL, of p38α or p38δ. We characterize role ternary complex formation driving selectivity, showing it is necessary, but insufficient, PROTAC-induced ubiquitination. Lastly, explore p38δ:PROTAC:VHL explain different profiles PROTACs. Our work attributes selective proteins same heretofore underappreciated aspects model.

Language: Английский

Citations

447