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Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold

DOI: 10.1016/j.ejmech.2020.112417 DOI Help

Authors: Chalada Suebsuwong (University of Houston; Icahn School of Medicine at Mount Sinai) , Bing Dai (Tufts University School of Medicine) , Daniel M. Pinkas (Structural Genomics Consortium, University of Oxford) , Anantha Lakshmi Duddupudi (University of Houston) , Li Li (University of Houston) , Joshua C. Bufton (Structural Genomic Consortium, Oxford University; University of Bristol) , Lisa Schlicher (Ludwig Institute for Cancer Research, University of Oxford) , Mads Gyrd-Hansen (Ludwig Institute for Cancer Research, University of Oxford) , Ming Hu (University of Houston) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Alexei Degterev (Tufts University School of Medicine) , Gregory D. Cuny (University of Houston)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 15433

Abstract: Receptor-interacting protein kinase 2 (RIPK2) is a key mediator of nucleotide-binding oligomerization domain (NOD) cell signaling that has been implicated in various chronic inflammatory conditions. A new class of RIPK2 kinase/NOD signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold was developed. Several co-crystal structures of RIPK2•inhibitor complexes were analyzed to provide insights into inhibitor selectivity versus the structurally related activin receptor-like kinase 2 (ALK2) demonstrating that the inhibitor sits deeper in the hydrophobic binding pocket of RIPK2 perturbing the orientation of the DFG motif. In addition, the structure-activity relationship study revealed that in addition to anchoring to the hinge and DFG via the 2-aminopyridine and 3-phenylsulfonamide, respectively, appropriate occupancy of the region between the gatekeeper and the αC-helix provided by substituents in the 4- and 5-positions of the 3-phenylsulfonamide were necessary to achieve potent NOD cell signaling inhibition. For example, compound 18t (e.g. CSLP37) displayed potent biochemical RIPK2 kinase inhibition (IC50 = 16 ± 5 nM), >20-fold selectivity versus ALK2 and potent NOD cell signaling inhibition (IC50 = 26 ± 4 nM) in the HEKBlue assay. Finally, in vitro ADME and pharmacokinetic characterization of 18t further supports the prospects of the 3,5-diphenyl-2-aminopyridine scaffold for the generation of in vivo pharmacology probes of RIPK2 kinase and NOD cell signaling functions.

Journal Keywords: Inhibitor; Kinase; NOD; Nucleotide-binding oligomerization domain; Receptor-interacting protein kinase; 2RIPK2

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

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 20/05/2020 10:47

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)