AI Article Synopsis
- Targeting the estrogen receptor alpha (ERα) pathway is a proven strategy for treating estrogen receptor-positive (ER+) breast cancers, leading to the development of a new type of drug called a PROTAC designed to degrade ERα.
- In laboratory tests, this PROTAC showed strong effectiveness in degrading ERα and blocking its activity in breast cancer cells, but results did not match when tested in live models.
- The discrepancy is attributed to the PROTAC’s linker being metabolically unstable, which leads to the creation of competing metabolites that interfere with the drug's ability to degrade ERα; this emphasizes the importance of designing more stable PROTACs for better treatment outcomes.
Article Abstract
Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091220 | PMC |
| http://dx.doi.org/10.1038/s42003-024-06238-x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A Focal Traumatic Injury to the Neonatal Rodent Spinal Cord Causes an Immediate and Massive Spreading Depolarization Sustained by Chloride Ions, with Transient Network Dysfunction.
Cell Mol Neurobiol
January 2025
Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste, TS, Italy.
In clinics, physical injuries to the spinal cord cause a temporary motor areflexia below lesion, known as spinal shock. This topic is still underexplored due to the lack of preclinical spinal cord injury (SCI) models that do not use anesthesia, which would affect spinal excitability. Our innovative design considered a custom-made micro impactor that provides localized and calibrated strikes to the ventral surface of the thoracic spinal cord of the entire CNS isolated from neonatal rats.
View Article and Find Full Text PDFINTEGRATING RADIOLOGICAL IMAGING TECHNIQUES INTO ANATOMY EDUCATION: MEDICAL TRAINING ENHANCEMANT THROUGH EARLY CT AND MRI TEACHING.
Probl Radiac Med Radiobiol
December 2024
ASST Ovest Milanese, Neuroimaging Unit, Legnano (Milan), Italy, 20025Centro Diagnostico Italiano S.p.A., Department of Diagnostic Imaging and Stereotactic Radiosurgery, Milan, Italy.
Unlabelled: Brain morphology understanding is essential for radiologists, neurologists, and neurosurgeons. Historically, anatomical learning of brain relied on ex vivo specimens. Modern in vivo brain CT and MRI provide spatial, three-dimensional imaging capabilities crucial to help diagnose diseases, plan surgeries, and monitor treatment progress.
View Article and Find Full Text PDFModularity-based mathematical modeling of ligand inter-nanocluster connectivity for unraveling reversible stem cell regulation.
Nat Commun
December 2024
Department of Materials Science and Engineering, Korea University, Seoul, Republic of Korea.
The native extracellular matrix is continuously remodeled to form complex interconnected network structures that reversibly regulate stem cell behaviors. Both regulation and understanding of its intricate dynamicity can help to modulate numerous cell behaviors. However, neither of these has yet been achieved due to the lack of designing and modeling such complex structures with dynamic controllability.
View Article and Find Full Text PDFContribution of the infection ecosystem and biogeography to antibiotic failure in vivo.
NPJ Antimicrob Resist
December 2024
Department of Biochemistry, University of Cambridge, Cambridge, UK.
The acquisition of antibiotic resistance in bacteria, though a deeply concerning international issue, is reasonably well-understood at a mechanistic level. Less well-understood is why bacteria that are sensitive in vitro to well-established and widely-used antibiotics sometimes fail to respond to these agents in vivo. This is a particularly common problem in chronic, polymicrobial infection scenarios.
View Article and Find Full Text PDF/ Value Determination for Penicillin-Binding Proteins in Live Cells.
ACS Infect Dis
December 2024
Department of Medicinal Chemistry, University of Minnesota, 208 Harvard Street SE, Minneapolis, Minnesota 55454, United States.
Article Synopsis
- - Penicillin-binding proteins (PBPs) are crucial bacterial enzymes that can be inhibited by β-lactam antibiotics, disrupting their ability to grow and divide, ultimately leading to cell lysis.
- - Traditional metrics like IC values for measuring enzyme inhibition can be misleading, especially for covalent inhibitors, making the second-order rate constant (k) a better measure of potency.
- - The researchers created a whole-cell k assay using a fluorescent probe to assess β-lactam potency across multiple PBPs, confirming its effectiveness in relation to existing IC values and supporting further structure-activity relationship studies.
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!