A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

Nature, Journal Year: 2016, Volume and Issue: 535(7611), P. 252 - 257

Published: June 22, 2016

Language: Английский

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Plasticity in binding confers selectivity in ligand-induced protein degradation

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

Published: June 8, 2018

Language: Английский

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PROTACs: great opportunities for academia and industry

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

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Advancing targeted protein degradation for cancer therapy

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(10), P. 638 - 654

Published: June 15, 2021

Language: Английский

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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Aug. 1, 2018

In historical attempts to treat morning sickness, use of the drug thalidomide led birth thousands children with severe defects. Despite their teratogenicity, and related IMiD drugs are now a mainstay cancer treatment; however, molecular basis underlying pleiotropic biology characteristic defects remains unknown. Here we show that IMiDs disrupt broad transcriptional network through induced degradation several C2H2 zinc finger transcription factors, including SALL4, member spalt-like family developmental factors. Strikingly, heterozygous loss function mutations in SALL4 result human condition phenocopies thalidomide-induced such as absence thumbs, phocomelia, ear eye development, congenital heart disease. We find induces exclusively humans, primates, rabbits, but not rodents or fish, providing mechanistic link for species-specific pathogenesis syndrome.

Language: Английский

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PROTACs: past, present and future

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(12), P. 5214 - 5236

Published: Jan. 1, 2022

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein interest (POI) and another can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI ligase results in ubiquitination subsequent degradation by ubiquitin-proteasome system (UPS). event-driven mechanism action (MOA) PROTACs offers several advantages compared traditional occupancy-driven small molecule inhibitors, such as catalytic nature, reduced dosing frequency, more potent longer-lasting effect, added layer selectivity reduce potential toxicity, efficacy face drug-resistance mechanisms, targeting nonenzymatic functions, expanded target space. Here, we highlight important milestones briefly discuss lessons learned about targeted (TPD) recent years conjecture on efforts still needed expand toolbox for PROTAC discovery ultimately provide promising therapeutics.

Language: Английский

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Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN

Science, Journal Year: 2018, Volume and Issue: 362(6414)

Published: Nov. 1, 2018

Thalidomide-targeted degradation Thalidomide and its analogs improve the survival of patients with multiple myeloma other blood cancers. Previous work showed that drugs bind to E3 ubiquitin ligase Cereblon, which then targets for two specific zinc finger (ZF) transcription factors a role in cancer development. Sievers et al. found more ZF proteins than anticipated are destabilized by thalidomide analogs. A proof-of-concept experiment revealed chemical modifications can lead selective proteins. The detailed information provided structural, biochemical, computational analyses could guide development target implicated human disease. Science , this issue p. eaat0572

Language: Английский

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Development of targeted protein degradation therapeutics

Nature Chemical Biology, Journal Year: 2019, Volume and Issue: 15(10), P. 937 - 944

Published: Sept. 16, 2019

Language: Английский

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Delineating the role of cooperativity in the design of potent PROTACs for BTK

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(31)

Published: July 16, 2018

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading ubiquitination subsequent degradation of the target. They present exciting opportunity modulate proteins in manner independent enzymatic or signaling activity. As such, they have recently emerged as attractive mechanism explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding parameters most critical for achieving potency selectivity. Here we employ series biochemical cellular techniques investigate requirements efficient knockdown Bruton's tyrosine kinase (BTK), nonreceptor essential B cell maturation. Members 11-compound PROTAC library were investigated their ability form binary ternary complexes with BTK cereblon (CRBN, ligase component). Results extended measure effects on BTK-CRBN cooperative interactions well vitro vivo degradation. Our data show alleviation steric clashes between CRBN by modulating linker length within chemical allows potent absence thermodynamic cooperativity.

Language: Английский

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Selective degradation of splicing factor CAPERα by anticancer sulfonamides

Nature Chemical Biology, Journal Year: 2017, Volume and Issue: 13(6), P. 675 - 680

Published: April 24, 2017

Language: Английский

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