NSC687852

(E/Z)-NSC-687852 is a isomer of NSC-687852 (HY-13989). NSC687852 (b-AP15) is a specific inhibitor of the deubiquitinating enzymes UCHL5 and Usp14[1].

This deubiquitinase inhibitor (FW = 421.31 g/mol; CAS 1009817-63-3), also named 3,5-bis[ (4-nitrophenyl) methylene]-1- (1-oxo-2-propen-1-yl) - (3E,5E) -4-piperidinone, targets two proteasome-associated ubiquitin carboxyl-terminal hydrolase-14, or USP14, and Ubiquitin Carboxyl-terminal Hydrolase isozyme L5 UCHL5, IC50 = 2.1 μM, resulting in a rapid accumulation of high-molecular-weight ubiquitin conjugates and functional shutdown of proteasome. Interestingly, b-AP15 displays several differences with respect to bortezomib including insensitivity to over-expression of the anti-apoptotic mediator Bcl-2 and anti-tumor activity in solid tumor models. Inhibition of DUBs blocked the processing and release of interleukin IL-1β in both mouse and human macrophages. DUB activity was necessary for inflammasome association as DUB inhibition also impaired ASC oligomerization and caspase-1 activation without directly blocking caspase- 1 activity. These data reveal the requirement for DUB activity in a key reaction of the innate immune response and highlight the therapeutic potential of DUB inhibitors for chronic auto-inflammatory diseases. (See also Bortezomib, Eeeyarestatin I)

[1] Berndtsson M, et al. Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system. Int J Cancer. 2009;124(6):1463-1469. DOI:10.1002/ijc.24004