☆ 4.7 Article

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Related references

Note: Only part of the references are listed.

Review Biotechnology & Applied Microbiology

PROTAC targeted protein degraders: the past is prologue

Miklos Bekes et al.

Summary: Targeted protein degradation (TPD) is a new therapeutic modality that can tackle disease-causing proteins which are difficult to target with conventional small molecules. PROTAC molecules, utilizing the ubiquitin-proteasome system to degrade target proteins, has achieved clinical proof-of-concept and attracted significant industry activity. Future directions include identifying target classes suitable for TPD, expanding the use of ubiquitin ligases for precision medicine, and extending the modality beyond oncology.

NATURE REVIEWS DRUG DISCOVERY (2022)

Add to Collection

Review Biochemistry & Molecular Biology

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

Zhenyi Hu et al.

Summary: PROTACs are an emerging technology that utilizes the ubiquitin-proteasome system for targeted protein degradation, showing great therapeutic potential in treating diseases. Over the past two decades, significant advancements have been made in PROTAC technology, with an increasing repertoire of targets.

CHEMBIOCHEM (2022)

Add to Collection

Review Biochemistry & Molecular Biology

BET bromodomain inhibitors

Martin P. Schwalm et al.

Summary: Lysine acetylation creates docking sites for epigenetic reader domains of BET bromodomain proteins, which are important regulators of linage specific gene transcription. The development of potent and selective inhibitors has facilitated mechanistic studies in disease models and translation into clinical practice. Advances in pan-BET inhibitors have led to second generation inhibitors with improved selectivity, as well as highly potent bifunctional and dual inhibitors, expanding the toolbox for research on acetylation dependent transcription, BET-associated diseases, and epigenetic reader domains.

CURRENT OPINION IN CHEMICAL BIOLOGY (2022)

Add to Collection

Article Chemistry, Medicinal

A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions

Le Guo et al.

Summary: PROTAC is a commonly used technology for targeted protein degradation, and the Rapid-TAC platform enables rapid synthesis of PROTAC through traceless coupling reaction, saving time and facilitating screening of active protein degraders.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2022)

Add to Collection

Article Chemistry, Medicinal

Designing Soluble PROTACs: Strategies and Preliminary Guidelines

Diego Garcia Jimenez et al.

Summary: Solubility optimization is crucial for obtaining oral PROTACs. Lipophilicity plays a major role in governing solubility, but the contribution of polarity cannot be neglected. By using infographic tools and machine learning, a privileged region for soluble PROTACs was identified, providing promising guidelines for optimizing PROTAC solubility.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Add to Collection

Article Pharmacology & Pharmacy

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression

Yuanfei Deng et al.

Summary: This study evaluates the anticancer activity of ARV-771 in hepatocellular carcinoma (HCC) and uncovers its mechanisms. ARV-771 suppresses HCC cell growth by arresting cell cycle progression and inducing apoptosis, while downregulating critical non-proteasomal deubiquitinases. Additionally, ARV-771 in combination with sorafenib can synergistically inhibit HCC cell growth.

FRONTIERS IN PHARMACOLOGY (2022)

Add to Collection

Article Multidisciplinary Sciences

Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases

Xin Luo et al.

Summary: The successful development of small molecule therapeutics that promote degradation of critical cancer targets has led to the investigation of bispecific molecules called PROTACs. This study aimed to elucidate the requirements for PROTAC activity and identify potential predictive biomarkers using a panel of 56 cell lines. The results showed that the expression and mutation status of VHL and CRBN were predictors of PROTAC activity in the cell line panel.

ISCIENCE (2022)

Add to Collection

Review Biochemistry & Molecular Biology

PROTACs for BRDs proteins in cancer therapy: a review

Chao Wang et al.

Summary: BRD proteins are important for regulating gene expression and are potential targets for therapeutic development. PROTACs, a new tool for therapeutic intervention, can remove disease-causing proteins. Small-molecule PROTACs based on BRD inhibitors have shown promise in cancer regulation.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY (2022)

Add to Collection

Article Chemistry, Medicinal

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

Alessandra Salerno et al.

Summary: PROTAC-mediated protein degradation has led to a rethink in drug discovery, with researchers proposing to enrich PROTACs with other therapeutic modalities to enhance efficacy, minimize side effects, and reach undruggable targets. The development of multifunctional PROTACs, such as multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates, and macrocycle-and oligonucleotide-based PROTACs, represents a promising approach to further enhance PROTAC effectiveness. Further steps are needed to advance the clinical investigation and translation of multifunctional PROTACs.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Add to Collection

Article Chemistry, Medicinal

Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation

Charles E. Hendrick et al.

Summary: A platform using a D2B approach has been developed to accelerate optimization of PROTACs through studying the linker effects. By synthesizing and characterizing a large number of linker analogs, the platform provides valuable information on the structure-activity relationships for in-cell target engagement, degradation, permeability, and cell toxicity. The platform has the potential to expand training sets for more complex prediction models.

ACS MEDICINAL CHEMISTRY LETTERS (2022)

Add to Collection

Review Chemistry, Multidisciplinary

Chemistries of bifunctional PROTAC degraders

Chaoguo Cao et al.

Summary: Proteolysis targeting chimeras (PROTACs) technology utilizes small molecules to induce ubiquitin-dependent degradation of proteins, offering a promising therapeutic strategy. However, the design and optimization of PROTACs face challenges, with a trial-and-error approach based on experience being the current general strategy. This review summarizes the principles and strategies for PROTACs design and optimization from the perspective of chemical structure design, and proposes potential future pathways for development.

CHEMICAL SOCIETY REVIEWS (2022)

Add to Collection

Article Chemistry, Medicinal

Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity

Victoria G. Klein et al.

Summary: The study explores the potential of enhancing PROTAC permeability and bioactivity by replacing amides with esters, leading to the design of novel VHL-based BET degraders. Ester PROTACs exhibited improved cell permeability and more potent protein degradation effects.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Add to Collection

Article Chemistry, Medicinal

Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta

Nan Bai et al.

Summary: PROTACs are molecules that induce target protein degradation by combining a target-binding warhead with an E3 ligase-recruiting moiety. A structure-based computational method has been developed to evaluate the suitability of linkers for ternary complex formation, which can explain PROTACs' activity and selectivity. Modeling ternary complex formation can help interpret PROTAC activity and reveal different binding modes within structurally conserved protein families.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2021)

Add to Collection

Article Multidisciplinary Sciences

Mutant-selective degradation by BRAF-targeting PROTACs

Shanique Alabi et al.

Summary: This study developed a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins. The new therapy demonstrates high selectivity and shows promising inhibitory effects on cancer cell growth in vivo.

NATURE COMMUNICATIONS (2021)

Add to Collection

Article Chemistry, Medicinal

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Alesa Bricelj et al.

Summary: The attachment points of CRBN ligands have a significant impact on their stability and degradation features, providing a blueprint for the development of future CRBN-based degraders with tailored properties.

ACS MEDICINAL CHEMISTRY LETTERS (2021)

Add to Collection

News Item Biotechnology & Applied Microbiology

Targeted protein degraders crowd into the clinic

Asher Mullard

NATURE REVIEWS DRUG DISCOVERY (2021)

Add to Collection

Article Chemistry, Organic

Tritylamine as an Ammonia Surrogate in the Ugi Reaction Provides Access to Unprecedented 5-Sulfamido Oxazoles Using Burgess-type Reagents

Irene Preet Bhela et al.

Summary: Starting from a variety of a-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents were utilized to enable cyclodehydration and produce unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety at the 5-position. The synthetic procedure makes use of readily available starting materials and proceeds smoothly under mild reaction conditions, demonstrating good tolerance for various functional groups and filling a research gap in the field of oxazole compounds.

ORGANIC LETTERS (2021)

Add to Collection

Review Chemistry, Multidisciplinary

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Carlotta Cecchini et al.

Summary: PROTACs are heterobifunctional degraders that eliminate targeted proteins by utilizing the UPS system, showing potential as an appealing technology in drug discovery. However, their poor cellular permeability due to high molecular weight and large polar surface area poses challenges, requiring strategies and biological tools to enhance cellular uptake.

FRONTIERS IN CHEMISTRY (2021)

Add to Collection

Article Chemistry, Medicinal

Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

Troy A. Bemis et al.

Summary: A current bottleneck in the development of PROTACs is the empirical nature of linker length structure-activity relationships. A multi-disciplinary approach has been detailed to alleviate this bottleneck. Research has focused on synthetic approaches to increase throughput, advances in structural biology and computational chemistry for rational PROTAC design, and de novo linker design in silico.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Add to Collection

Article Biotechnology & Applied Microbiology

The PROTACtable genome

Melanie Schneider et al.

Summary: This article presents a systematic approach to assessing the PROTAC tractability of protein targets, which could support decision-making on whether a particular target may be amenable to modulation using a PROTAC.

NATURE REVIEWS DRUG DISCOVERY (2021)

Add to Collection

Review Chemistry, Multidisciplinary

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

Alesa Bricelj et al.

Summary: PROTACs, as a new and exciting class of therapeutic agents, consist of target binding units, linkers, and E3 ligase binding moieties, leading to ubiquitination and proteasomal degradation of target proteins through the chemically-induced formation of ternary complexes. This review provides in-depth analysis on the synthetic preparation of functionalized ligands for relevant E3 ligases, highlighting the importance of understanding preparative routes and chemistry of linker attachment for the assembly of final PROTACs.

FRONTIERS IN CHEMISTRY (2021)

Add to Collection

Article Chemistry, Multidisciplinary

The 100 facets of the Passerini reaction

Luca Banfi et al.

Summary: This perspective celebrates the 100th anniversary of the discovery of the Passerini three component reaction, highlighting its importance and application in organic synthesis. The focus of this review is on the various ways to expand the utility of the Passerini reaction.

CHEMICAL SCIENCE (2021)

Add to Collection

Review Biochemistry & Molecular Biology

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

Michael J. Bond et al.

Summary: The discovery of PROTACs has revolutionized targeted protein degradation, leading to the development of orally bioavailable clinical drugs. Future advancements in technology will expedite the discovery of new degraders and E3 ligases, as well as the identification of active degraders.

RSC CHEMICAL BIOLOGY (2021)

Add to Collection

Review Oncology

Advancing targeted protein degradation for cancer therapy

Brandon Dale et al.

Summary: The development of small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) has enabled the targeting of previously considered undruggable oncoproteins. This review discusses recent advances in the field, with a focus on opportunities and challenges for future development.

NATURE REVIEWS CANCER (2021)

Add to Collection

Article Chemistry, Multidisciplinary

Rapid synthesis of pomalidomide-conjugates for the development of protein degrader libraries

Duncan K. Brownsey et al.

Summary: This study presents a reliable and high-yielding strategy for preparing heterobifunctional pomalidomide-linkers, utilizing the trend of secondary amines providing higher yields than primary amines. Results show that this trend can be exploited to prepare high-yield pomalidomide homo-dimers and develop a new one-pot synthesis method for JQ1-pomalidomide conjugates.

CHEMICAL SCIENCE (2021)

Add to Collection

Article Chemistry, Multidisciplinary

Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants

Troy A. Bemis et al.

Summary: This article demonstrates a rapid assembly approach for PROTAC variants using activated esters and Staudinger ligation. By testing previously studied systems, the feasibility of the synthetic method is verified, and two strategies for assembling PROTAC linker variants are discussed.

CHEMICAL COMMUNICATIONS (2021)

Add to Collection

Article Pharmacology & Pharmacy

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1

Mingxing Hu et al.

ACTA PHARMACEUTICA SINICA B (2020)

Add to Collection

Review Pharmacology & Pharmacy

Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective

Andy Pike et al.

DRUG DISCOVERY TODAY (2020)

Add to Collection

Article Chemistry, Medicinal

PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes

Daniel Zaidman et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2020)

Add to Collection

Article Chemistry, Medicinal

Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

Laura Goracci et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

Add to Collection

Review Chemistry, Multidisciplinary

Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications

Manar Ahmed Fouad et al.

RSC ADVANCES (2020)

Add to Collection

Article Chemistry, Multidisciplinary

A more sustainable and highly practicable synthesis of aliphatic isocyanides

K. A. Waibel et al.

GREEN CHEMISTRY (2020)

Add to Collection

Review Chemistry, Medicinal

Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges

Scott D. Edmondson et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2019)

Add to Collection

Article Biochemistry & Molecular Biology

BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design

William Farnaby et al.

NATURE CHEMICAL BIOLOGY (2019)

Add to Collection

Article Biochemistry & Molecular Biology

Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway

Philipp Ottis et al.

ACS CHEMICAL BIOLOGY (2019)

Add to Collection

Article Chemistry, Medicinal

Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

Xin Han et al.

JOURNAL OF MEDICINAL CHEMISTRY (2019)

Add to Collection

Article Chemistry, Multidisciplinary

Solid-phase synthesis for thalidomide-based proteolysis-targeting chimeras (PROTAC)

S. Krajcovicova et al.

CHEMICAL COMMUNICATIONS (2019)

Add to Collection

Article Chemistry, Multidisciplinary

PROTAC-mediated crosstalk between E3 ligases

Christian Steinebach et al.

CHEMICAL COMMUNICATIONS (2019)

Add to Collection

Article Chemistry, Medicinal

A Click Chemistry Platform for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation

Ryan P. Wurz et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

Add to Collection

Article Biochemistry & Molecular Biology

Plasticity in binding confers selectivity in ligand-induced protein degradation

Radoslaw P. Nowak et al.

NATURE CHEMICAL BIOLOGY (2018)

Add to Collection

Review Biotechnology & Applied Microbiology

Induced protein degradation: an emerging drug discovery paradigm

Ashton C. Lai et al.

NATURE REVIEWS DRUG DISCOVERY (2017)

Add to Collection

Review Biochemistry & Molecular Biology

Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders

Scott J. Hughes et al.

STRUCTURE-BASED DRUG DESIGN: INSIGHTS FROM ACADEMIA AND INDUSTRY (2017)

Add to Collection

Article Biochemistry & Molecular Biology

Structural basis of PROTAC cooperative recognition for selective protein degradation

Morgan S. Gadd et al.

NATURE CHEMICAL BIOLOGY (2017)

Add to Collection

Article Chemistry, Multidisciplinary

Split-Ugi Reaction with Chiral Compounds: Synthesis of Piperazine- and Bispidine-Based Peptidomimetics

Mattia Stucchi et al.

HELVETICA CHIMICA ACTA (2016)

Add to Collection

Article Biochemistry & Molecular Biology

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

Jing Lu et al.

CHEMISTRY & BIOLOGY (2015)

Add to Collection

Article Biochemistry & Molecular Biology

Catalytic in vivo protein knockdown by small-molecule PROTACs

Daniel P. Bondeson et al.

NATURE CHEMICAL BIOLOGY (2015)

Add to Collection

Article Multidisciplinary Sciences

Phthalimide conjugation as a strategy for in vivo target protein degradation

Georg E. Winter et al.

SCIENCE (2015)

Add to Collection

Article Chemistry, Multidisciplinary

The homo-PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α-Oxo- or α-Hydroxy-γ-acylaminoamides and Chromanes

Fabio Morana et al.

CHEMISTRY-A EUROPEAN JOURNAL (2013)

Add to Collection

Article Chemistry, Multidisciplinary

A mimicry of primary amines by bis-secondary diamines as components in the Ugi four-component reaction

GB Giovenzana et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2006)

Add to Collection

Article Multidisciplinary Sciences

Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation

KM Sakamoto et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2001)

Add to Collection

© Peeref 2019-2024. All rights reserved.