IndraLab

"Other studies have also found that b-AP15 inhibition of USP14 and UCHL5 triggers apoptosis in MM cell lines in a time dependent and dose dependent manner.77 Similar cytotoxic effects, as those seen with b-AP15 treatment, occur within myeloma cells when treated with an alternative DUB inhibitor, copper pyrithione.77 Targeting E1 ubiquitin activating enzyme and E3 ubiquitin ligases has synergistic activity with bortezomib on cell lines.78, 79 An inhibitor of USP7, P5091, can interfere with ubiquitin binding and overcome bortezomib resistance invitro and invivo.80 NIMA related kinase 2 (NEK2) overexpression is associated with resistance to multiple drugs and poor prognosis in MM, and NEK2 inhibitor has been shown to decrease proteasome activity.81 Further investigation into its role in Bortezomib resistance is required."

"Our recent study exemplifies the feasibility of such an approach : specifically, we showed that blockade of 19S associated DUBs USP14 and UCHL5 with a small-molecule inhibitor (bAP15 and VLX1570) induces apoptosis in MM cells and overcome bortezomib resistance, with a favorable toxicity profile."

"b-AP15 is a specific UCHL5 and USP14 inhibitor identified from a screening of small molecules that induce the lysosomal apoptosis pathway."