RIP1 Kinase Inhibitor III

A cell-permeable furopyrimidinyl-phenyl urea compound that potently inhibits RIP1 kinase activity (IC₅₀ = 13 nM; [ATP] = 50 µM) by targeting RIPK1 ATP-binding pocket in its inactive DLG-out conformation (IC₅₀ = 63 nM in competitive binding assays against 5 nM ATP-site ligand) without affecting RIPK2 or RIPK5 activity even at concentrations as high as 1 µM ([ATP] = 10 µM). Effectively prevents TNFα-induced necroptosis in Z-VAD(OMe)-FMK- (Cat. No. 627610) treated U937 cultures (EC₅₀ = 250 nM) in vitro and is efficacious in protecting mice from body temperature loss (by 77%; 20 mg/kg p.o.) when administered 15 min prior to TNFα i.v. injection in vivo with good oral availability (plasma C_max = 1100 ng/mL, T_max = 4 h, AUC = 14 µg·h/mL; 2 mg/kg p.o.). Selectivity profiling in a 300-kinase panel shows significant inhibition against only 25 targets (IC₅₀<1 µM), notably RET, EPHA7, FLT3, EPHA6, HIPK4, DDR2, FMS, PDGFRa, and TrkC (% inhibition at 1 µM = 97%, 97%, 96%, 92%, 91%, 90%, 86%, 84%, 84%, respectively).

A cell-permeable, orally available furopyrimidinyl-phenyl urea compound that acts as a potent and reversible inhibitor of receptor interacting protein 1 (RIP1) kinase (IC₅₀ = 63 nM and 13 nM in RIP fluorescence polarization and ADP-Glo kinase assays, respectively). Binds to the ATP-binding pocket of RIP1 kinase with enzyme adopting a DLG-out inactive conformation. Shown to be moderately effective in inhibiting 25 other protein kinases in a screening of 300 kinases by radiolabeled assay, but only at high concentrations (~ 1 µM in the presence of 10 mM ATP). Blocks TNFα-induced necrotic cell death (IC₅₀ = 250 nM in U937 cells) and protects mice from TNFα-induced hypothermic shock when injected 15 min. prior to i.v. administration of TNFα. Displays desirable pharmacokinetic properties with good systemic exposure following an oral dose (AUC= 14 mg/h/ml; C_max = 1,100 ng/ml at 4 hours).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

A cell-permeable, potent, reversible inhibitor of RIP1 kinase (IC₅₀ = 63 nM in RIP fluorescence polarization assay).

Cell permeable: yes

Primary Target
RIP1 Kinase

Following reconstitution, aliquot and freeze (-20°C).

Use only fresh DMSO for reconstitution.

Harris, P.A., et al. 2013. ACS Med. Chem. Lett.4, 1238.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)