☆ 4.8 Review

Translational PK-PD for targeted protein degradation

CHEMICAL SOCIETY REVIEWS (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

Article Pharmacology & Pharmacy

A kinetic proofreading model for bispecific protein degraders

Derek W. Bartlett et al.

Summary: The study describes a mechanistic modeling framework for bispecific protein degraders (BPDs) that involves ternary complex formation and degradation via the ubiquitin-proteasome system. A multi-step process in the model results in a time delay, balancing ternary complex stability and proteasome degradation rates. This concept applies kinetic proofreading in a quantitative pharmacokinetic-pharmacodynamic framework to inform the design of potent and selective BPDs.

JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS (2021)

Add to Collection

Article Biochemistry & Molecular Biology

Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes

James Schiemer et al.

Summary: Heterobifunctional chimeric degraders are ligands that recruit target proteins to E3 ubiquitin ligases to induce protein degradation. This study characterized degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1 using biochemical, biophysical and structural studies, revealing new insights and showing that increased ternary complex stability or rigidity does not always correlate with increased degradation efficiency.

NATURE CHEMICAL BIOLOGY (2021)

Add to Collection

Review Physiology

History and Future Perspectives on the Discipline of Quantitative Systems Pharmacology Modeling and Its Applications

Karim Azer et al.

Summary: This paper reviews the history of mathematical biology and pharmacology models, highlights some gaps and challenges in the development and application of systems pharmacology models, and proposes an integrated strategy to overcome these challenges by leveraging advances in adjacent fields.

FRONTIERS IN PHYSIOLOGY (2021)

Add to Collection

Article Chemistry, Multidisciplinary

Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

Robert P. Law et al.

Summary: This study introduced a novel FAK-degrading PROTAC, GSK215, designed based on VHL E3 ligase and the FAK inhibitor VS-4718, showing promising potential for a differentiated clinical strategy in cancer treatment compared to conventional FAK inhibition. The highly cooperative FAK-GSK215-VHL ternary complex revealed by X-ray crystallography provided insights into the molecular basis of the compound's efficacy. In mouse models, GSK215 demonstrated rapid and prolonged FAK degradation, highlighting its potential as a valuable tool for studying FAK-degradation biology in vivo.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021)

Add to Collection

Review Pharmacology & Pharmacy

The rise and rise of protein degradation: Opportunities and challenges ahead

Scott J. Hughes et al.

Summary: Targeted protein degradation strategies, such as PROTACs, have shown potential for potent in vivo pharmacology, but there are still opportunities for further improvement. Expanding knowledge may lead to the discovery of new degrading mechanisms to address limitations and improve efficiency, drug-like properties, and resistance to current approaches. Further advancements in TPD utility are possible through potential routes discussed in the study.

DRUG DISCOVERY TODAY (2021)

Add to Collection

Article Chemistry, Multidisciplinary

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Frances P. Rodriguez-Rivera et al.

Summary: Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, lowering administered doses and extending pharmacological effects. However, a holistic framework that evaluates different degradation modes from a catalytic perspective is currently lacking.

ACS CENTRAL SCIENCE (2021)

Add to Collection

Review Biochemistry & Molecular Biology

The role of reversible and irreversible covalent chemistry in targeted protein degradation

Hannah Kiely-Collins et al.

Summary: PROTACs are an exciting technology in chemical biology and drug discovery that degrade disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system. This review explores the role of reversible and irreversible covalent chemistry in targeted protein degradation, highlighting the key advantages of targeted covalent inhibitors. They enhance the selectivity of PROTACs, enable access to more of the undruggable proteome, and expand the repertoire of recruited E3 ligases.

CELL CHEMICAL BIOLOGY (2021)

Add to Collection

Review Biochemistry & Molecular Biology

Targeted protein degradation: A promise for undruggable proteins

Kusal T. G. Samarasinghe et al.

Summary: Protein homeostasis is crucial for maintaining a balanced, healthy environment within cells, but excessive dysregulated proteins can lead to disease. PROTACs and other Targeted Protein Degradation (TPD) strategies are emerging as potential therapeutic modalities for degrading disease-causing proteins, including previously undruggable targets like transcription factors.

CELL CHEMICAL BIOLOGY (2021)

Add to Collection

Article Chemistry, Multidisciplinary

Structure-Based Design of a Macrocyclic PROTAC

Andrea Testa et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2020)

Add to Collection

Article Chemistry, Multidisciplinary

Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs

Ronen Gabizon et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2020)

Add to Collection

Review Biochemistry & Molecular Biology

Examining Targeted Protein Degradation from Physiological and Analytical Perspectives: Enabling Translation between Cells and Subjects

Natalie A. Daurio et al.

ACS CHEMICAL BIOLOGY (2020)

Add to Collection

Article Biochemistry & Molecular Biology

A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands

Bomie Han

JOURNAL OF BIOLOGICAL CHEMISTRY (2020)

Add to Collection

Article Multidisciplinary Sciences

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

Wen-Hao Guo et al.

NATURE COMMUNICATIONS (2020)

Add to Collection

Article Biology

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Alina Mares et al.

COMMUNICATIONS BIOLOGY (2020)

Add to Collection

Article Multidisciplinary Sciences

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

Blake E. Smith et al.

NATURE COMMUNICATIONS (2019)

Add to Collection

Article Biochemistry & Molecular Biology

SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate

Michael J. Roy et al.

ACS CHEMICAL BIOLOGY (2019)

Add to Collection

Review Biochemistry & Molecular Biology

Targeted protein degradation and the enzymology of degraders

Stewart L. Fisher et al.

CURRENT OPINION IN CHEMICAL BIOLOGY (2018)

Add to Collection

Article Multidisciplinary Sciences

Delineating the role of cooperativity in the design of potent PROTACs for BTK

Adelajda Zorba et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2018)

Add to Collection

Article Biochemistry & Molecular Biology

Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action

Kristin M. Riching et al.

ACS CHEMICAL BIOLOGY (2018)

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

Review Biochemistry & Molecular Biology

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Philipp M. Cromm et al.

CELL CHEMICAL BIOLOGY (2017)

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 Chemistry, Multidisciplinary

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

Eugene F. Douglass et al.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2013)

Add to Collection

© Peeref 2019-2024. All rights reserved.