{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nikhar S"],"funding":["NIA NIH HHS","NIAID NIH HHS","NCI NIH HHS","NINDS NIH HHS","National Institutes of Health","Wellcome Trust"],"pagination":["113252"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8009825"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["215"],"pubmed_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 (IC<sub>50</sub> = 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 (IC<sub>50</sub> = 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. C<sub>max</sub> = 5.7 μM, T<sub>max</sub> = 15 min, t<sub>1/2</sub> = 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."],"journal":["European journal of medicinal chemistry"],"pubmed_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."],"pmcid":["PMC8009825"],"funding_grant_id":["R21 AI124049","R01 AI144400","R21 NS111395","R56 AG058642","R01 CA190542","102894/Z/13/Z"],"pubmed_authors":["Degterev A","Lee S","Siokas I","Gyrd-Hansen M","Nikhar S","Schlicher L","Cuny GD"],"additional_accession":[]},"is_claimable":false,"name":"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.","description":"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 (IC<sub>50</sub> = 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 (IC<sub>50</sub> = 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. C<sub>max</sub> = 5.7 μM, T<sub>max</sub> = 15 min, t<sub>1/2</sub> = 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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Apr","modification":"2026-05-31T13:01:27.458Z","creation":"2025-04-06T21:54:13.19Z"},"accession":"S-EPMC8009825","cross_references":{"pubmed":["33601309"],"doi":["10.1016/j.ejmech.2021.113252"]}}