1. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2
- Author
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Jenni Cryan, Don T. Fisher, Michael Reilly, Ian Edward David Smith, Anna Vossenkämper, Gillian F. Watt, Ian Churcher, John D. Harling, Allison M. Beal, Thomas T. MacDonald, Alina Mares, Phoebe Dace, Bartholomew J. Votta, Marcus Bantscheff, Jane Denyer, Paul Scott-Stevens, Afjal Hussain Miah, Andrew B. Benowitz, Aditya R. Thawani, Carol A. Capriotti, Mark David Rackham, Nico Zinn, and Pamela A. Haile
- 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 - 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., 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.
- Published
- 2020