Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Cell, Journal Year: 2020, Volume and Issue: 183(6), P. 1714 - 1731.e10

Published: Dec. 1, 2020

Language: Английский

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Degradation of proteins by PROTACs and other strategies

Acta Pharmaceutica Sinica B, Journal Year: 2019, Volume and Issue: 10(2), P. 207 - 238

Published: Aug. 13, 2019

Blocking the biological functions of scaffold proteins and aggregated is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be solution, considering its ability to selectively degrade target proteins. Recent progress in strategy include identification structure first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), ARV-110 has entered clinical trials for treatment prostate cancer 2019. These discoveries strongly proved value strategy. In this perspective, we summarized recent meaningful research PROTAC, including types degradation proteins, preliminary data vitro vivo, new E3 ubiquitin ligases. Importantly, molecular design, optimization application candidate molecules are highlighted detail. Future perspectives development advanced medical fields have also been discussed systematically.

Language: Английский

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Current strategies for the design of PROTAC linkers: a critical review

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2020, Volume and Issue: 1(5)

Published: Oct. 11, 2020

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind E3 ubiquitin ligase and a “warhead” protein interest, connected by chemical linker. Targeted degradation PROTACs has emerged as new modality for the knock down range proteins, with first agents now reaching clinical evaluation. It become increasingly clear that length composition linker play critical roles on physicochemical properties bioactivity PROTACs. While design historically received limited attention, PROTAC field is evolving rapidly currently undergoing important shift from synthetically tractable alkyl polyethylene glycol more sophisticated functional linkers. This promises unlock wealth novel enhanced therapeutic intervention. Here, authors provide timely overview diverse classes in published literature, along their underlying principles overall influence associated Finally, analysis current strategies assembly. The highlight limitations traditional “trial error” approach around selection, suggest potential future avenues further inform rational accelerate identification optimised In particular, believe advances computational structural methods will essential role gain better understanding structure dynamics ternary complexes, be address gaps knowledge design.

Language: Английский

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Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

ACS Central Science, Journal Year: 2019, Volume and Issue: 5(10), P. 1682 - 1690

Published: Sept. 17, 2019

Off-tissue effects are persistent issues of modern inhibition-based therapies. By merging the strategies photopharmacology and small-molecule degraders, we introduce a novel concept for spatiotemporal control induced protein degradation that potentially prevents off-tissue toxicity. Building on successful principle bifunctional all-small-molecule Proteolysis Targeting Chimeras (PROTACs), designed photoswitchable PROTACs (

Language: Английский

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Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Nature, Journal Year: 2021, Volume and Issue: 601(7893), P. 434 - 439

Published: Dec. 22, 2021

Abstract The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling 1 and is altered over 20% of cancers 2,3 . Here we developed proteolysis-targeting chimera (PROTAC) degrader the SWI/SNF ATPase subunits, SMARCA2 SMARCA4, called AU-15330. Androgen receptor (AR) + forkhead box A1 (FOXA1) prostate cancer cells are exquisitely sensitive to dual SMARCA4 degradation relative normal other cell lines. rapidly compacts cis -regulatory elements bound by transcription factors that drive proliferation, namely AR, FOXA1, ERG MYC, which dislodges them from chromatin, disables their core enhancer circuitry, abolishes downstream oncogenic gene programs. also disrupts super-enhancer promoter looping interactions wire supra-physiologic expression AR , FOXA1 MYC oncogenes themselves. AU-15330 induces potent inhibition tumour growth xenograft models synergizes with antagonist enzalutamide, even inducing disease remission castration-resistant (CRPC) without toxicity. Thus, impeding SWI/SNF-mediated accessibility represents promising therapeutic approach for enhancer-addicted cancers.

Language: Английский

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Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 62(24), P. 11218 - 11231

Published: Dec. 5, 2019

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using antagonist E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in discovery 11 (ARD-266), which effectively induces degradation protein AR-positive (AR+) LNCaP, VCaP, 22Rv1 cell lines DC50 values 0.2–1 nM. ARD-266 capable reducing level by >95% these AR+ reduces AR-regulated gene expression suppression. For first time, we demonstrated that an ligand micromolar affinity its complex can be successfully employed design efficient PROTAC this finding may have significant implication field research.

Language: Английский

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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics

Oncogene, Journal Year: 2020, Volume and Issue: 39(26), P. 4909 - 4924

Published: May 31, 2020

Language: Английский

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

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100647 - 100647

Published: Jan. 1, 2021

Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool therapeutic modality. By co-opting pathways, TPD facilitates complete removal of the molecules from within or outside cell. While pioneering Proteolysis-Targeting Chimera (PROTAC) technology molecular glues hijack ubiquitin-proteasome system, newer modalities co-opt autophagy endo-lysosomal pathway. Using this mechanism, is posited to largely expand druggable space far beyond small-molecule inhibitors. In review, we discuss major advances in TPD, highlight our current understanding, explore outstanding questions field.

Language: Английский

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Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: April 11, 2022

Abstract Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target and E3 ubiquitin ligase together to trigger proteasomal degradation of by the ubiquitin-proteasome system. has emerged as a promising approach therapy in various diseases, particularly cancers. In this review, we introduce principle development technology, well advantages PROTACs over traditional anti-cancer therapies. Moreover, summarize application targeting critical oncoproteins, provide guidelines molecular design discuss challenges PROTACs.

Language: Английский

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Targeted protein degradation: A promise for undruggable proteins

Cell chemical biology, Journal Year: 2021, Volume and Issue: 28(7), P. 934 - 951

Published: May 17, 2021

Language: Английский

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