Small-molecule modulators of protein activity are increasingly being utilized as tools to examine the functional roles of proteins. Operating at the post-translational level, these molecules provide enhanced temporal and spatial control and mitigate the potential for compensatory responses in comparison with classical genetic approaches. Proteolysis targeting chimeric molecules, or PROTACs, are small molecules that inhibit the function of their target proteins by targeting them for degradation by the ubiquitin proteasome system. This chapter summarizes strategies for PROTAC preparation and characterization.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852687 | PMC |
| http://dx.doi.org/10.1007/978-1-61779-474-2_44 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
ET-PROTACs: modeling ternary complex interactions using cross-modal learning and ternary attention for accurate PROTAC-induced degradation prediction.
Brief Bioinform
November 2024
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410003, China.
Motivation: Accurately predicting the degradation capabilities of proteolysis-targeting chimeras (PROTACs) for given target proteins and E3 ligases is important for PROTAC design. The distinctive ternary structure of PROTACs presents a challenge to traditional drug-target interaction prediction methods, necessitating more innovative approaches. While current state-of-the-art (SOTA) methods using graph neural networks (GNNs) can discern the molecular structure of PROTACs and proteins, thus enabling the efficient prediction of PROTACs' degradation capabilities, they rely heavily on limited crystal structure data of the POI-PROTAC-E3 ternary complex.
View Article and Find Full Text PDFRationalize the Functional Roles of Protein-Protein Interactions in Targeted Protein Degradation by Kinetic Monte Carlo Simulations.
J Phys Chem B
December 2024
Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States.
Targeted protein degradation is a promising therapeutic strategy to tackle disease-causing proteins that lack binding pockets for traditional small-molecule inhibitors. Its first step is to trigger the proximity between a ubiquitin ligase complex and a target protein through a heterobifunctional molecule, such as proteolysis targeting chimeras (PROTACs), leading to the formation of a ternary complex. The properties of protein-protein interactions play an important regulatory role during this process, which can be reflected by binding cooperativity.
View Article and Find Full Text PDFDual targeting and bioresponsive nano-PROTAC induced precise and effective lung cancer therapy.
J Nanobiotechnology
November 2024
The Fifth Affiliated Hospital, The Affiliated Panyu Central Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, The School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
Epigenetic regulation has emerged as a promising therapeutic strategy for lung cancer treatment, which can facilitate the antitumor responses by modulating epigenetic dysregulation of target proteins in lung cancer. The proteolysis-targeting chimera (PROTAC) reagent, dBET6 shows effective inhibition of bromodomain-containing protein 4 (BRD4) that exerts antitumor efficacy by degrading BRD4 via the ubiquitin-proteasome system. Nevertheless, the low tissue specificity and bioavailability impede its therapeutic effects and clinical translation on lung cancer treatment.
View Article and Find Full Text PDFAdvances in designing ternary complexes: Integrating in-silico and biochemical methods for PROTAC optimisation in target protein degradation.
Bioorg Chem
December 2024
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India. Electronic address:
Target protein degradation (TPD) is an emerging approach to mitigate disease-causing proteins. TPD contains several strategies, and one of the strategies that gained immersive importance in recent times is Proteolysis Targeting Chimeras (PROTACs); the PROTACs recruit small molecules to induce the poly-ubiquitination of disease-causing protein by hijacking the ubiquitin-proteasome system (UPS) by bringing the E3 ligase and protein of interest (POI) into appropriate proximity. The steps involved in designing and evaluating the PROTACs remain critical in optimising the PROTACs to degrade the POI.
View Article and Find Full Text PDFEfficient PROTAC-ing: combinational use of PROTACs with signaling pathway inhibitors.
Trends Biochem Sci
November 2024
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address:
Article Synopsis
- Targeted protein degradation is a new treatment approach focused on destroying proteins that cause diseases.* -
- A study by Mori et al. utilized high-throughput screening to find small molecules that can inhibit specific cellular processes.* -
- These inhibitors boost the effectiveness of PROTACs, which are designed to promote the degradation of unwanted proteins.*
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!