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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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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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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PHOTACs enable optical control of protein degradation

Science Advances, Journal Year: 2020, Volume and Issue: 6(8)

Published: Feb. 21, 2020

We present a modular approach to control the small molecule–mediated degradation of cellular proteins interest using light.

Language: Английский

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Light-induced control of protein destruction by opto-PROTAC

Science Advances, Journal Year: 2020, Volume and Issue: 6(8)

Published: Feb. 21, 2020

Opto-PROTAC adds a light-inducible switch on PROTAC, enabling optical control for targeted degradation of proteins interest .

Language: Английский

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Cancer Selective Target Degradation by Folate-Caged PROTACs

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(19), P. 7380 - 7387

Published: May 10, 2021

PROTACs (proteolysis targeting chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin–proteasome system. However, potential toxicity in normal cells due to off-tissue on-target degradation effect limits their clinical applications. Precise control a PROTAC's activity tissue-selective manner could minimize toxicity/side-effects. To this end, we developed cancer cell selective delivery strategy for conjugating folate group ligand VHL E3 ubiquitin ligase, achieve targeted proteins interest (POIs) versus noncancerous cells. We show our folate-PROTACs, including BRD PROTAC (folate-ARV-771), MEK (folate-MS432), and ALK (folate-MS99), capable degrading BRDs, MEKs, ALK, respectively, receptor-dependent This design provides generalizable platform POIs

Language: Английский

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