b-AP15

Proteasome-associated deubiquitinases (DUBs) release ubiquitin from proteasome-targeted ubiquitinated proteins, regenerating free ubiquitin.¹ b-AP15 is an inhibitor of ubiquitin-specific-processing protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5), two proteasome-associated DUBs.² It inhibits DUB activity in purified 19S proteasomes with an IC₅₀ value of 2.1 µM.² It exhibits little or no activity against several other DUBs.² Through its effects on USP14 and UCHL5, b-AP15 blocks tumor progression in vivo in mice and prevents organ infiltration in mouse models of myeloid leukemia.^2,3 b-AP15 also renders tumor cells sensitive to TNF-mediated apoptosis by natural killer and T cells.⁴

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1. Zhang, W., and Sidhu, S.S. Development of inhibitors in the ubiquitination cascade. FEBS Lett. 588(2), 356-367 (2014).

2. D'Arcy, P., Brnjic, S., Olofsson, M.H., et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat. Med. 17(12), 1636-1640 (2011).

3. Tian, Z., D'Arcy, P., Wang, X., et al. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 123(5), 706-716 (2014).

4. Sarhan, D., Wennerberg, E., D'Arcy, P., et al. A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer Immunol. Immunother. 62(8), 1359-1368 (2013).