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Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel. | LitMetric

AI Article Synopsis

  • RIP2 kinase is a promising therapeutic target for autoimmune diseases, and a specific 4-aminoquinoline-based inhibitor has shown effectiveness in blocking NOD2 signaling across various biological models.* -
  • The initial inhibitor faced issues with off-target effects at the hERG ion channel and had a poor pharmacokinetic/pharmacodynamic (PK/PD) profile, limiting its further development.* -
  • Recent improvements to the inhibitor have enhanced its binding affinity to RIP2 (IC = 1 nM) and reduced hERG activity (14 μM), while also effectively inhibiting cytokine production in human blood (IC = 10 nM).*

Article Abstract

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor , which possesses high binding affinity for the ATP pocket of RIP2 (IC = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC = 10 nM) with reduced hERG activity (14 μM).

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187414PMC
http://dx.doi.org/10.1021/acsmedchemlett.8b00344DOI Listing

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