GW806742X hydrochloride, an ATP mimetic and a potent MLKL (Mixed Lineage Kinase Domain-Like protein) inhibitor, binds the MLKL pseudokinase domain with a Kd of 9.3 μM. GW806742X hydrochloride has activity against VEGFR2 (IC50=2 nM). GW806742X hydrochloride retards MLKL membrane translocation and inhibits necroptosis[1][2].
GW806742X (0.1-10000 nM) inhibits necroptotic death of wild-type mouse dermal fibroblasts (MDFs) stimulated with TSQ (1 ng/mL TNF, 500 nM compound A (Smac mimetic), 10 μM Q-VD-OPh) in a dose-dependent manner[1].GW806742X shows inhibition of VEGF induced proliferation of HUVECs with an IC50 of 5 nM[2].
[1]. Hildebrand JM, et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014;111(42):15072-15077. [2]. Sammond DM, et al. Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase. Bioorg Med Chem Lett. 2005;15(15):3519-3523.