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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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. / Nikhar, Sameer; Siokas, Ioannis; Schlicher, Lisa; Lee, Seungheon; Gyrd-Hansen, Mads; Degterev, Alexei; Cuny, Gregory D.

In: European Journal of Medicinal Chemistry, Vol. 215, 113252, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Nikhar, S, Siokas, I, Schlicher, L, Lee, S, Gyrd-Hansen, M, Degterev, A & Cuny, GD 2021, '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', European Journal of Medicinal Chemistry, vol. 215, 113252. https://doi.org/10.1016/j.ejmech.2021.113252

APA

Nikhar, S., Siokas, I., Schlicher, L., Lee, S., Gyrd-Hansen, M., Degterev, A., & Cuny, G. D. (2021). 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. European Journal of Medicinal Chemistry, 215, [113252]. https://doi.org/10.1016/j.ejmech.2021.113252

Vancouver

Nikhar S, Siokas I, Schlicher L, Lee S, Gyrd-Hansen M, Degterev A et al. 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. European Journal of Medicinal Chemistry. 2021;215. 113252. https://doi.org/10.1016/j.ejmech.2021.113252

Author

Nikhar, Sameer ; Siokas, Ioannis ; Schlicher, Lisa ; Lee, Seungheon ; Gyrd-Hansen, Mads ; Degterev, Alexei ; Cuny, Gregory D. / 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. In: European Journal of Medicinal Chemistry. 2021 ; Vol. 215.

Bibtex

@article{71990dee898c4524b52f8afaf800caf7,
title = "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",
abstract = "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.",
keywords = "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",
author = "Sameer Nikhar and Ioannis Siokas and Lisa Schlicher and Seungheon Lee and Mads Gyrd-Hansen and Alexei Degterev and Cuny, {Gregory D}",
note = "Copyright {\textcopyright} 2021 Elsevier Masson SAS. All rights reserved.",
year = "2021",
doi = "10.1016/j.ejmech.2021.113252",
language = "English",
volume = "215",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson",

}

RIS

TY - JOUR

T1 - 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

AU - Nikhar, Sameer

AU - Siokas, Ioannis

AU - Schlicher, Lisa

AU - Lee, Seungheon

AU - Gyrd-Hansen, Mads

AU - Degterev, Alexei

AU - Cuny, Gregory D

N1 - Copyright © 2021 Elsevier Masson SAS. All rights reserved.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/chemical synthesis

KW - Cell Line, Tumor

KW - Drug Design

KW - Humans

KW - Molecular Docking Simulation

KW - Nod2 Signaling Adaptor Protein/antagonists & inhibitors

KW - Protein Binding

KW - Protein Domains

KW - Protein Kinase Inhibitors/chemical synthesis

KW - Pyridines/chemical synthesis

KW - Pyrimidinones/chemical synthesis

KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors

KW - Signal Transduction/drug effects

U2 - 10.1016/j.ejmech.2021.113252

DO - 10.1016/j.ejmech.2021.113252

M3 - Journal article

C2 - 33601309

VL - 215

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 113252

ER -

ID: 280715305