RIP1 Inhibitor II, 7-Cl-O-Nec-1

A cell-permeable 7-chloroindolylmethyl-hydantoin that exhibits highly RIP1-selective inhibitory activity among >400 human kinases and is superior to its structural analog Necrostatin-1 (Cat. No. 480065) in blocking RIP1-dependent necroptosis due to improved potency (EC₅₀ = 206 nM vs. 494 nM with Nec-1 for protecting FADD-deficient Jurkat from 30 h 10 ng/mL TNF-α-induced death), selectivity (no inhibition against IDO/indolamine 2,3-deoxygenase vs. IC₅₀ = 11.4 µM with Nec-1), metabolic stability, as well as reduced in vitro and in vivo toxicity. In addition, 7-Cl-O-Nec-1 is reported to exhibit blood-brain barrier permeability in mice (Brain and plasma conc. = 0.74 and 0.31 µM, respectively, 30 min post 1 mg/6.25 mL/kg i.v. injection using male mice) and is efficacious in reducing brain infarct size when applied via intracerebroventricular injections (63% of control size 18 h post occlusion; two 8 nmol/2 µL/mouse injections at 4 h & 6 h post occlusion) in a murine MCAO model in vivo.

Cell permeable: yes

Primary Target
RIP1

Reversible: yes

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Use only fresh DMSO for reconstitution.

Ofengeim, D., et al. 2015. Cell Reports10, In press.
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Degterev, A., et al. 2013. Cell Death Differ.20, 366.
Christofferson, D.E., et al. 2012. Cell Death Dis.3, e320.
Takahashi, N., et al. 2012. Cell Death Dis.3, e437.
Degterev, A., et al. 2008. Nat. Chem. Biol.4, 313.
Degterev, A., et al. 2005. Nat. Chem. Biol.1, 112.
Teng, X., et al. 2005. Bioorg. Med. Chem. Lett.15, 5039.

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

Toxicity: Standard Handling (A)