Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic DOI
Zhenyi Hu, Craig M. Crews

ChemBioChem, Год журнала: 2021, Номер 23(2)

Опубликована: Сен. 8, 2021

Abstract Proteolysis‐targeting chimeras (PROTACs), an emerging paradigm‐shifting technology, hijacks the ubiquitin‐proteasome system for targeted protein degradation. PROTACs induce ternary complexes between E3 ligase and POI, this induced proximity leads to polyUb chain formation on substrates eventual proteasomal‐mediated POI have shown great therapeutic potential by degrading many disease‐causing proteins, such as androgen receptor BRD4. The PROTAC technology has advanced significantly in last two decades, with repertoire of targets increased tremendously. Herein, we describe recent developments focusing mechanistic kinetic studies, pharmacokinetic study, spatiotemporal control PROTACs, covalent resistance new ligands.

Язык: Английский

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

и другие.

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(3), С. 181 - 200

Опубликована: Янв. 18, 2022

Язык: Английский

Процитировано

1926

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

и другие.

Nature Reviews Drug Discovery, Год журнала: 2019, Номер 18(12), С. 949 - 963

Опубликована: Окт. 30, 2019

Язык: Английский

Процитировано

726

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

Mariell Pettersson,

Craig M. Crews

Drug Discovery Today Technologies, Год журнала: 2019, Номер 31, С. 15 - 27

Опубликована: Фев. 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.

Язык: Английский

Процитировано

616

An open-source drug discovery platform enables ultra-large virtual screens DOI
Christoph Gorgulla, Andras Boeszoermenyi, Zifu Wang

и другие.

Nature, Год журнала: 2020, Номер 580(7805), С. 663 - 668

Опубликована: Март 9, 2020

Язык: Английский

Процитировано

533

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

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2019, Номер 4(1)

Опубликована: Дек. 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.

Язык: Английский

Процитировано

522

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

Current Opinion in Chemical Biology, Год журнала: 2019, Номер 50, С. 111 - 119

Опубликована: Апрель 17, 2019

Язык: Английский

Процитировано

488

Targeted protein degradation: mechanisms, strategies and application DOI Creative Commons
Lin Zhao, Jia Zhao,

Kunhong Zhong

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Апрель 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Язык: Английский

Процитировано

446

Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1 DOI Creative Commons
Adam D. Cotton, Duy Nguyen, Josef A. Gramespacher

и другие.

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(2), С. 593 - 598

Опубликована: Янв. 4, 2021

Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase target of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies membrane-bound ligases for cell-surface proteins. We show AbTAC can induce lysosomal programmed death-ligand 1 by recruitment RNF43. AbTACs represent archetype within PROTAC field proteins with biological molecules.

Язык: Английский

Процитировано

352

PROTACs: An Emerging Therapeutic Modality in Precision Medicine DOI Creative Commons

Dhanusha A. Nalawansha,

Craig M. Crews

Cell chemical biology, Год журнала: 2020, Номер 27(8), С. 998 - 1014

Опубликована: Авг. 1, 2020

Язык: Английский

Процитировано

345

Nrf2/Keap1/ARE signaling: Towards specific regulation DOI Open Access
A. V. Ulasov, Andrey A. Rosenkranz,

Georgii P. Georgiev

и другие.

Life Sciences, Год журнала: 2021, Номер 291, С. 120111 - 120111

Опубликована: Окт. 31, 2021

Язык: Английский

Процитировано

336