Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold
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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. / Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N; Degterev, Alexei; Cuny, Gregory D.
In: European Journal of Medicinal Chemistry, Vol. 200, 112417, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold
AU - Suebsuwong, Chalada
AU - Dai, Bing
AU - Pinkas, Daniel M
AU - Duddupudi, Anantha Lakshmi
AU - Li, Li
AU - Bufton, Joshua C
AU - Schlicher, Lisa
AU - Gyrd-Hansen, Mads
AU - Hu, Ming
AU - Bullock, Alex N
AU - Degterev, Alexei
AU - Cuny, Gregory D
N1 - Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Aminopyridines/chemistry
KW - Binding Sites
KW - Crystallography, X-Ray
KW - Humans
KW - Inflammation
KW - Nod Signaling Adaptor Proteins/chemistry
KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/chemistry
KW - Signal Transduction/drug effects
KW - Structure-Activity Relationship
U2 - 10.1016/j.ejmech.2020.112417
DO - 10.1016/j.ejmech.2020.112417
M3 - Journal article
C2 - 32505849
VL - 200
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 112417
ER -
ID: 280716359