Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling
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Receptor interacting protein kinase-2 (RIPK2) is an enzyme involved in the transduction of pro-inflammatory nucleotide-binding oligomerization domain (NOD) cell signaling, a pathway implicated in numerous chronic inflammatory conditions. Herein, a pyrido[2,3-d]pyrimidin-7-one based class of RIPK2 kinase and NOD2 cell signaling inhibitors is described. For example, 33 (e.g. UH15-15) inhibited RIPK2 kinase (IC50 = 8 ± 4 nM) and displayed > 300-fold selectivity versus structurally related activin receptor-like kinase 2 (ALK2). This molecule blocked NOD2-dependent HEKBlue NF-κB activation (IC50 = 20 ± 5 nM) and CXCL8 production (at concentrations > 10 nM). Molecular docking suggests that engagement of Ser25 in the glycine-rich loop may provide increased selectivity versus ALK2 and optimal occupancy of the region between the gatekeeper and the αC-helix may contribute to potent NOD2 cell signaling inhibition. Finally, this compound also demonstrated favorable in vitro ADME and pharmacokinetic properties (e.g. Cmax = 5.7 μM, Tmax = 15 min, t1/2 = 3.4 h and Cl = 45 mL/min/kg following single 10 mg/kg intraperitoneal administration) further supporting the use of pyrido[2,3-d]pyrimidin-7-ones as a new structure class of RIPK2 kinase and NOD cell signaling inhibitors.
Original language | English |
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Article number | 113252 |
Journal | European Journal of Medicinal Chemistry |
Volume | 215 |
ISSN | 0223-5234 |
DOIs | |
Publication status | Published - 2021 |
Externally published | Yes |
Bibliographical note
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
- Antineoplastic Agents/chemical synthesis, Cell Line, Tumor, Drug Design, Humans, Molecular Docking Simulation, Nod2 Signaling Adaptor Protein/antagonists & inhibitors, Protein Binding, Protein Domains, Protein Kinase Inhibitors/chemical synthesis, Pyridines/chemical synthesis, Pyrimidinones/chemical synthesis, Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors, Signal Transduction/drug effects
Research areas
ID: 280715305