Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Commun Biol. 2020 Mar 20;3(1):140. doi: 10.1038/s42003-020-0868-6.

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / enzymology
  • Crohn Disease / drug therapy
  • Crohn Disease / enzymology
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Stability
  • Female
  • Humans
  • Inflammation / enzymology
  • Inflammation / immunology
  • Inflammation / prevention & control*
  • Inflammation Mediators / metabolism
  • Injections, Intravenous
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / enzymology
  • Male
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism*
  • THP-1 Cells
  • Tissue Culture Techniques
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Inflammation Mediators
  • Ubiquitin-Protein Ligases
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Proteasome Endopeptidase Complex