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Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2
- Source :
- Communications Biology, Vol 3, Iss 1, Pp 1-13 (2020), Communications Biology
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.<br />Mares et al. develop Proteolysis-Targeting Chimeras (PROTACs) that degrade its target RIPK2 in vivo at low doses for a prolonged period of time. This study suggests that PROTAC has a therapeutic potential that is superior to traditional RIPK2 small-molecule inhibitors.
- Subjects :
- Male
THP-1 Cells
Anti-Inflammatory Agents
Medicine (miscellaneous)
Medicinal chemistry
Pharmacology
01 natural sciences
Serine
Rats, Sprague-Dawley
Tissue Culture Techniques
Ubiquitin
Crohn Disease
Enzyme Stability
lcsh:QH301-705.5
0303 health sciences
biology
medicine.diagnostic_test
Drug discovery
Chemistry
Ubiquitin ligase
Injections, Intravenous
Cytokines
Female
medicine.symptom
Inflammation Mediators
General Agricultural and Biological Sciences
Proteasome Endopeptidase Complex
Proteolysis
Ubiquitin-Protein Ligases
General Biochemistry, Genetics and Molecular Biology
Article
RIPK2
03 medical and health sciences
Receptor-Interacting Protein Serine-Threonine Kinase 2
medicine
Animals
Humans
Pharmacokinetics
Rats, Wistar
Protein kinase A
030304 developmental biology
Inflammation
Dose-Response Relationship, Drug
010405 organic chemistry
Ubiquitination
0104 chemical sciences
Mechanism of action
Pharmacodynamics
lcsh:Biology (General)
Drug Design
biology.protein
Leukocytes, Mononuclear
Colitis, Ulcerative
Subjects
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 3
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Communications Biology
- Accession number :
- edsair.doi.dedup.....db0dc940ac613e6d44979be8bc358056