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A Small Molecule Inhibitor of Ubiquitin-Specific protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

A Small Molecule Inhibitor of Ubiquitin-Specific protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Dharminder Chauhan, Ze Tian, Benjamin Nicholson, K G Suresh Kumar, Bin Zhou, Ruben Carrasco, Jeffrey L McDermott, Craig A Leach, Mariaterresa Fulcinniti, Matthew P Kodrasov, Joseph Weinstock, William D Kingsbury, etc.

Cancer Cell. 2012 Sep 11;22(3):345-58.

PMID: 22975377

Abstract:

Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP882257116	P5091		882257-11-6	Price

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