☆ 4.7 Article

A Mechanistic Pharmacodynamic Modeling Framework for the Assessment and Optimization of Proteolysis Targeting Chimeras (PROTACs)

PHARMACEUTICS (2023)

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 Chemistry, Medicinal

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma

Jingyu Zhang et al.

Summary: In this study, dimensionality reduction analysis and model molecule validation were used to identify key structural features for improving the oral absorption of BTK-PROTACs. The newly discovered BTK-PROTACs B1 and B2 were optimized based on the results. Compound C13 with improved oral bioavailability, high BTK degradation activity, and selectivity was discovered. It showed inhibitory effects against hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTKPROTAC for the treatment of lymphoma.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Add to Collection

Review Biochemistry & Molecular Biology

Recent Advances of Degradation Technologies Based on PROTAC Mechanism

Mingchao Xiao et al.

Summary: This article introduces PROTAC technology and the recent advances in novel degradation technologies based on this mechanism. It discusses the clinical progress, current challenges, and future prospects of degradation technologies based on the PROTAC mechanism.

BIOMOLECULES (2022)

Add to Collection

Review Chemistry, Multidisciplinary

PROTACs: past, present and future

Ke Li et al.

Summary: PROTACs are a type of molecules with novel event-driven mechanism, offering multiple advantages over traditional inhibitors, such as catalytic nature and targeted protein degradation, which may lead to improved therapeutic outcomes with reduced toxicity. However, further research and development efforts are needed to fully explore their potential.

CHEMICAL SOCIETY REVIEWS (2022)

Add to Collection

Review Chemistry, Multidisciplinary

Translational PK-PD for targeted protein degradation

Derek W. Bartlett et al.

Summary: Targeted protein degradation has emerged as an exciting area for therapeutic development in the pharmaceutical industry. This review provides practical insights for understanding the pharmacokinetic and pharmacodynamic properties of protein degraders, and offers a roadmap for their translational development. By using quantitative mathematical frameworks and standard experimental assays, this review highlights the unique characteristics of protein degraders and their potential in drug development.

CHEMICAL SOCIETY REVIEWS (2022)

Add to Collection

Editorial Material Pharmacology & Pharmacy

Perspective on model-informed drug development

Lawrence J. Lesko

Summary: Model-informed drug development (MIDD) is a process that utilizes quantitative modeling and simulation technology to expedite drug development, enhance regulatory science, and provide benefits for patients. MIDD was codified in the 2017 Prescription Drug User Fee Act Reauthorization and includes a pilot program to hold industry-U.S. FDA meetings quarterly through 2022.

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY (2021)

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 Biochemical Research Methods

Target Validation Using PROTACs: Applying the Four Pillars Framework

Radoslaw P. Nowak et al.

Summary: Proteolysis targeting chimeras (PROTACs) are emerging as a promising strategy for targeted protein degradation in drug discovery. However, challenges such as complex physicochemistry and the development of orally bioavailable drugs need to be addressed for PROTACs to reach their full potential.

SLAS DISCOVERY (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 Biochemical Research Methods

A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination

Ellen F. Vieux et al.

Summary: This work developed an in vitro system to measure the kinetics of BRD4 BD1 ubiquitination and characterized the affinities between BiDACs, BD1, and CRBN, providing a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.

SLAS DISCOVERY (2021)

Add to Collection

Article Chemistry, Medicinal

Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Xin Han et al.

Summary: This study outlines strategies for discovering highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics, successfully identifying compound ARD-2128 as the most effective in inhibiting tumor growth in mice with good oral bioavailability.

JOURNAL OF MEDICINAL CHEMISTRY (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

Article Biochemical Research Methods

Flexible Fitting of PROTAC Concentration-Response Curves with Changepoint Gaussian Processes

Elizaveta Semenova et al.

Summary: PROTAC is a novel technology for protein degradation with high specificity. The study utilized a Bayesian changepoint Gaussian processes model to fit different types of CR curves, reducing subjective influence. This method reduces time and cost in compound ranking procedures, ensuring the reliability of experimental results.

SLAS DISCOVERY (2021)

Add to Collection

Review Chemistry, Multidisciplinary

Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective

Laura M. Luh et al.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2020)

Add to Collection

Review Pharmacology & Pharmacy

Fundamental aspects of DMPK optimization of targeted protein degraders

Carina Cantrill et al.

DRUG DISCOVERY TODAY (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 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 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 Chemistry, Medicinal

Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)

Jiantao Hu et al.

JOURNAL OF MEDICINAL CHEMISTRY (2019)

Add to Collection

Article Pharmacology & Pharmacy

Model-Informed Drug Discovery and Development: Current Industry Good Practice and Regulatory Expectations and Future Perspectives

Scott Marshall et al.

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY (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 Multidisciplinary Sciences

Systematic analysis of protein turnover in primary cells

Toby Mathieson et al.

NATURE COMMUNICATIONS (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

Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead

Daniel P. Bondeson et al.

CELL 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

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

Prolonged and tunable residence time using reversible covalent kinase inhibitors

J. Michael Bradshaw et al.

NATURE CHEMICAL 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

Review Pharmacology & Pharmacy

Model-based drug discovery: implementation and impact

Sandra A. G. Visser et al.

DRUG DISCOVERY TODAY (2013)

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

Article Multidisciplinary Sciences

Detection of sequential polyubiquitylation on a millisecond timescale

Nathan W. Pierce et al.

NATURE (2009)

Add to Collection

© Peeref 2019-2024. All rights reserved.