Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

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

Published: Jan. 16, 2020

Language: Английский

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Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

Chemical Reviews, Journal Year: 2020, Volume and Issue: 120(24), P. 13135 - 13272

Published: Oct. 30, 2020

Photoactivatable (alternatively, photoremovable, photoreleasable, or photocleavable) protecting groups (PPGs), also known as caged photocaged compounds, are used to enable non-invasive spatiotemporal photochemical control over the release of species interest. Recent years have seen development PPGs activatable by biologically and chemically benign visible near-infrared (NIR) light. These long-wavelength-absorbing moieties expand applicability this powerful method its accessibility non-specialist users. This review comprehensively covers organic transition metal-containing photoactivatable compounds (complexes) that absorb in visible- NIR-range various leaving gasotransmitters (carbon monoxide, nitric oxide, hydrogen sulfide). The text NIR-light-induced photosensitized using molecular sensitizers, quantum dots, upconversion second-harmonic nanoparticles, well via photodynamic (photooxygenation singlet oxygen) photothermal effects. Release from polymers, micelles, vesicles, photoswitches, along with related emerging field photopharmacology, is discussed at end review.

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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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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PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Cell chemical biology, Journal Year: 2020, Volume and Issue: 27(8), P. 998 - 1014

Published: Aug. 1, 2020

Language: Английский

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Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: May 13, 2020

Abstract Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of ligand (mostly small-molecule inhibitor) the interest (POI) and covalently linked an E3 ubiquitin ligase (E3). Upon binding POI, can recruit POI ubiquitination, which is subjected proteasome-mediated complements nucleic acid-based gene knockdown/out technologies reduction could mimic pharmacological inhibition. To date, PROTACs targeting ~ 50 proteins, many are clinically validated drug targets, have successfully with several in clinical trials cancer therapy. This article reviews PROTAC-mediated degradation critical oncoproteins cancer, particularly those hematological malignancies. Chemical structures, cellular vivo activities, pharmacokinetics, pharmacodynamics these summarized. In addition, potential advantages, challenges, perspectives therapy discussed.

Language: Английский

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The extracellular matrix in development

Development, Journal Year: 2020, Volume and Issue: 147(10)

Published: May 15, 2020

ABSTRACT As the crucial non-cellular component of tissues, extracellular matrix (ECM) provides both physical support and signaling regulation to cells. Some ECM molecules provide a fibrillar environment around cells, while others sheet-like basement membrane scaffold beneath epithelial In this Review, we focus on recent studies investigating mechanical, biophysical cues provided developing tissues by different types in variety organisms. addition, discuss how helps regulate tissue morphology during embryonic development governing key elements cell shape, adhesion, migration differentiation.

Language: Английский

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Cell cycle on the crossroad of tumorigenesis and cancer therapy

Trends in Cell Biology, Journal Year: 2021, Volume and Issue: 32(1), P. 30 - 44

Published: July 22, 2021

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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On the Promise of Photopharmacology Using Photoswitches: A Medicinal Chemist’s Perspective

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(20), P. 11436 - 11447

Published: June 8, 2020

Photopharmacology is a growing area of endeavor that employs photoswitchable ligands to allow for light-dependent pharmacological activity. By coupling light therapeutic action, improved spatial and temporal selectivity can be achieved subsequently harnessed new concepts in therapy. Tremendous progress has already been made, with photopharmacological agents now reported against wide array target classes results demonstrated range live cell animal models. Several challenges remain, however, especially order photopharmacology truly impact the clinical management disease. This Perspective aims summarize these challenges, particularly attention medicinal chemistry will unavoidably required further translation agents/approaches. clearly defining drug hunters, it hoped research into stimulated, ultimately enabling full realization huge potential this exciting field.

Language: Английский

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