Abstract A21: Inhibition of USP7 for the treatment of multiple myeloma and other malignancies.

The conjugation and deconjugation of ubiquitin controls the stability, localization and activity of many cellular proteins. Deconjugation of ubiquitin is performed by a family of ~80 deubiquitylating enzymes (DUBs) including USP7 which specifically removes ubiquitin from HDM2, Foxp3, claspin and other therapeutically relevant substrates. Importantly, USP7 is overexpressed in human multiple myeloma cells and the expression level of USP7 inversely correlates with prognosis in multiple myeloma patients. Previously, we reported the discovery and characterization of P0005091 a USP7 inhibitor which exhibited anti-tumor activity in in vitro and in vivo models of multiple myeloma. Additionally, we reported that P0005091 inhibits USP47 a closely related DUB which is an emerging oncology target in its own right. Furthermore, a structural analog of P0005091, P0022077 has recently been reported by another research group to inhibit neuroblastoma growth in an orthotopic mouse model suggesting that in addition to hematological tumors, solid tumors may be treatable via inhibition of USP7. To obtain additional starting points for a USP7 or a USP7/USP47 specific drug discovery program we recently performed a new screening campaign. By utilizing a biophysical assay platform we were able to exclude compounds that bind to the active site of USP7 thus increasing the possibility of identifying allosteric modifiers of USP7 activity. Hits from this screen are currently the subject of hit to lead optimization and will be evaluated in biophysical and biochemical assays as well as in vitro and in vivo models of hematological malignancies. Data will be presented describing these results. Citation Format: Benjamin Nicholson, Matthew P. Kodrasov, James P. LaRocque, Michael J. Eddins, Suresh Kumar, Dharminder Chauhan, Kenneth C. Anderson, Michael R. Mattern. Inhibition of USP7 for the treatment of multiple myeloma and other malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A21.