b-AP15

b-AP15 is a specific deubiquitinase (DUB) inhibitor. It inhibits ubiquitin-specific-processing protease 14 (USP14) and ubiquitin c-terminal hydrolase isozyme L5 (UCHL5, UCH37), two 19S regulatory particle proteasome-associated DUBs. It exhibits minimal inhibition of UCHL-1, UCHL-3, USP2, USP7, USP and BAP1. Has been described to inhibit also the 20S proteasome with an IC50 comparable to that required for inhibiting the 19S regulatory particles. b-AP15 has anticancer properties and blocks tumor progression in vivo in mice and prevents organ infiltration in mouse models of myeloid leukemia. b-AP15 also renders tumor cells sensitive to TNF-mediated apoptosis by natural killer and T cells. It induces apoptosis, ER stress and autophagy in several cancer cells. b-AP15 has anti-inflammatory properties inhibiting ERK1/2 and JNK phosphorylation, increasing IkappaBalpha levels and inhibiting NF-kappaB p65. b-AP15 inhibits the LPS/ATP-induced deubiquitination of NLRP3 and further increases NLRP3 ubiquitination. This leads to inhibition of NLRP3 activation, indicating that deubiquitination of NLRP3 by the priming and activation signals is critical for its activation.