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Identification of quinoline-based RIP2 kinase inhibitors with an improved therapeutic index to the hERG ion channel

DOI: 10.1021/acsmedchemlett.8b00344 DOI Help

Authors: Pamela A. Haile (GlaxoSmithKline) , Linda N. Casillas (GlaxoSmithKline) , Michael J. Bury (GlaxoSmithKline) , John F. Mehlmann (GlaxoSmithKline) , Robert Singhaus (GlaxoSmithKline) , Adam K. Charnley (GlaxoSmithKline) , Terry V. Hughes (GlaxoSmithKline) , Michael P. Demartino (GlaxoSmithKline) , Gren Z. Wang (GlaxoSmithKline) , Joseph J. Romano (GlaxoSmithKline) , Xiaoyang Dong (GlaxoSmithKline) , Nikolay V. Plotnikov (GlaxoSmithKline) , Ami S. Lakdawala (GlaxoSmithKline) , Maire A. Convery (GlaxoSmithKline) , Bartholomew J. Votta (GlaxoSmithKline) , David B. Lipshutz (GlaxoSmithKline) , Biva M. Desai (GlaxoSmithKline) , Barbara Swift (GlaxoSmithKline) , Carol A. Capriotti (GlaxoSmithKline) , Scott B. Berger (GlaxoSmithKline) , Mukesh K. Mahajan (GlaxoSmithKline) , Michael A. Reilly (GlaxoSmithKline) , Elizabeth J. Rivera (GlaxoSmithKline) , Helen H. Sun (GlaxoSmithKline) , Rakesh Nagilla (GlaxoSmithKline) , Carol Lepage (GlaxoSmithKline) , Michael T. Ouellette (GlaxoSmithKline) , Rachel D. Totoritis (GlaxoSmithKline) , Brian T. Donovan (GlaxoSmithKline) , Barry S. Brown (GlaxoSmithKline) , Khuram W. Chaudhary (GlaxoSmithKline) , Peter J. Gough (GlaxoSmithKline) , John Bertin (GlaxoSmithKline) , Robert W. Marquis (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 1195

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 GSK583 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 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).

Journal Keywords: hERG; kinase inhibitor; NOD1; NOD2; RIP2

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography