p97 ATPase Activity Inhibitor, DBeQ

A cell-permeable quinazolinamine compound that inhibits the AAA (ATPase associated with diverse cellular activities) ATPase p97 (IC₅₀ = 1.6 µM against WT or C522A p97) in a reversible and ATP-competitive (K_i = 3.2 µM) manner, while being at least 50-fold less potent against AAA ATPase NSF (N-methylmaleimide-sensitive factor) or the ATP-dependent chymotrypsin-like activity of proteasome 20S, and exhibiting no significant activity against a panel of ~170 kinases. Shown to effectively suppress p97-dependent cellular processes, including ERAD (ER-associated degradation) reporter TCRα-GFP degradation (92.59% vs. 33.33% degradation in 2 h, respectively, with DMSO or 10 µM DBeQ in HEK293 cultures), autophagic degradation of LC3-II (LC3-II/LC3-I = 0.04 vs. 1.0, respectively, after 3 h DMSO or 10 µM DBeQ treatment in HeLa cultures), UFD (ubiquitin fusion degradation) pathway-mediated Ub^G76V-GFP reporter degradation (IC₅₀ = 2.3 µM in HeLa cells), but not the degradation of p97-independent proteasome substrates ODC (ornithine decarboxylase) and ODD (oxygen-dependent degradation domain of HIF-1α) luciferase fusion reporters (IC₅₀ = 45 and 56 µM, respectively, in HeLa cells). Also demonstrated to display selective antiproliferative activity against RPMI8226, HeLa, and HEK293 over non-cancerous human fetal lung fibroblasts MRC5 (GI₅₀ = 1.2, 3.1, 4.0, and 6.6 µM, respectively) by inducing cellular DEVD-like (caspase-3/7), but not VEID-like (caspase-6), activity (by 4- to 6-fold in 4 h in HeLa cells) via a yet unknown mechanism.

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Chou, T.F., et al. 2011. Proc. Natl. Acad. Sci. USA108, 4834.

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

Toxicity: Regulatory Review (Z)