P005091

P005091 is a trisubstituted thiophene that inhibits USP7 and the closely related USP47 (EC₅₀s = 4.2 and 4.3 μM, respectively) with little activity against other classes of proteases, including caspases, cathepsins, calpain, metalloproteases, and serine proteases (EC₅₀s = > 100 μM).^1,2 P005091 has been shown to accelerate the degradation of the USP7 substrate HDM2 in several multiple myeloma cell lines (EC₅₀ = 11 μM) and to inhibit the growth of HCT116 human colorectal cancer cells (EC₅₀ = 11 μM) synergistically with doxorubicin, etoposide, or mechlorethamine.¹ In vivo, 10 mg/kg P005091 prolongs survival and reduces tumor growth in mice bearing human multiple myeloma and B cell leukemia xenografts.¹

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1. Chauhan, D., Tian, Z., Nicholson, B., et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22(3), 345-358 (2012).

2. Weinstock, J., Wu, J., Cao, P., et al. Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47. ACS Med. Chem. Lett. 3, 789-792 (2012).