PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such cancer, immune disorders, viral infections, neurodegenerative diseases, but also provide unique chemical knockdown tools biological research catalytic, reversible, rapid manner. In 2019, our group published review article “PROTACs: great opportunities academia industry” journal, summarizing representative compounds reported before end 2019. past 2 years, entire field protein experienced development, including large increase number papers on small-molecule degraders have entered will enter stage. addition PROTAC molecular glue technology, other technologies are developing rapidly. this article, we mainly summarize related targets 2020–2021 present researchers exciting developments degradation. The problems need solved briefly introduced.

Language: Английский

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Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

RSC Chemical Biology, Journal Year: 2021, Volume and Issue: 2(3), P. 725 - 742

Published: Jan. 1, 2021

With the discovery of PROteolysis TArgeting Chimeras (PROTACs) twenty years ago, targeted protein degradation (TPD) has changed landscape drug development.

Language: Английский

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Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic

ChemBioChem, Journal Year: 2021, Volume and Issue: 23(2)

Published: Sept. 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.

Language: Английский

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Target and tissue selectivity of PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(14), P. 5740 - 5756

Published: Jan. 1, 2022

In this review, we focus on recent progress towards making selective PROTAC molecules and new technologies that will continue to push the boundaries of achieving target tissue selectivity.

Language: Английский

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Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2576 - 2607

Published: Feb. 17, 2021

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform field medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) chemical literature, enable controlled degradation specific their direction cellular proteasome. In this report, we describe second phase our research focused on exploring antibody–drug conjugates (ADCs), which incorporate BRD4-targeting degrader entities. We employ new BRD4-binding fragment construction ADC payloads is significantly more potent than corresponding entity utilized initial studies. The resulting BRD4-degrader antibody exhibit and antigen-dependent BRD4 antiproliferation activities cell-based experiments. Multiple ADCs bearing also strong, antitumor efficacy mouse xenograft assessments several different tumor models.

Language: Английский

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Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(19), P. 8216 - 8257

Published: Jan. 1, 2022

This review provides a comprehensive overview of the structure-based design small-molecule VHL ligands and their applications as inhibitors E3 ligase recruiting moieties in PROTAC degraders.

Language: Английский

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Payload diversification: a key step in the development of antibody–drug conjugates

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Jan. 17, 2023

Abstract Antibody–drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity monoclonal antibodies with potency payload consisting cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at forefront ADC development. The recent approval clinical success trastuzumab deruxtecan (Enhertu ® ) sacituzumab govitecan (Trodelvy ), two topoisomerase 1 inhibitor-based ADCs, has shown potential conjugating unconventional payloads differentiated mechanisms action. Among future developments in field, diversification expected to play key role as illustrated by growing number preclinical stage payload-conjugated ADCs. This review presents comprehensive overview validated, forgotten newly developed different

Language: Английский

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Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 26, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific degradation. The POLY-PROTACs are engineered covalently grafting small molecular onto backbone an amphiphilic diblock copolymer via disulfide bonds. self-assemble into micellar nanoparticles and sequentially respond extracellular matrix metalloproteinase-2, intracellular acidic reductive microenvironment. POLY-PROTAC NPs further functionalized with azide groups bioorthogonal click reaction-amplified delivery tissue. For proof-of-concept, demonstrate that BRD4 degradation nanoplatform combine photodynamic therapy efficiently regress xenografts in a mouse model MDA-MB-231 breast cancer. This study suggests potential precise PROTAC-based cancer therapy.

Language: Английский

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Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2534 - 2575

Published: Feb. 17, 2021

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) related chimeric molecules that effect intracellular degradation target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these entities are relatively large compounds often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation such monoclonal antibodies using technologies originally developed for cytotoxic payloads so as provide alternate delivery options novel agents. In this report, we describe first phase our systematic development antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting degrader entities. demonstrate antigen-dependent PC3-S1 prostate cancer cells along with on MYC transcription BRD4 levels. These experiments culminate identification one conjugate, exhibits antiproliferation effects LNCaP cells.

Language: Английский

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Antibody–drug conjugates: Recent advances in payloads

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(10), P. 4025 - 4059

Published: June 30, 2023

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads efficient killing, show great clinical therapeutic value. The ADCs' play a key role in determining efficacy ADC drugs thus have attracted attention field. An ideal payload should possess sufficient toxicity, low immunogenicity, high stability, modifiable functional groups. Common include tubulin inhibitors DNA damaging agents, accounting for more than half development. However, due to limitations traditional payloads, such as inadequate development acquired drug resistance, novel highly diverse targets reduced side effects are being developed. This perspective summarizes recent research advances main focuses on structure-activity relationship studies, co-crystal structures, designing strategies, further discusses future directions payloads. review also aims provide valuable references that will efficacy, adequate abilities overcome resistance.

Language: Английский

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