Abstract 5432: Discovery and Characterization of USP22 Inhibitors As Novel Anti-Cancer Agents

Abstract The degradation of most cellular proteins is regulated by coordinated addition and removal of ubiquitin by families of ubiquitin E3 ligases and deubiquitylating enzymes (DUBs) respectively. DUBs proteolytically cleave ubiquitin molecules from proteins resulting in modifications of protein activity, localization and function. Several DUBs are aberrantly regulated in cancer, including the best studied, USP7, selective inhibitors of which are active in cancer models. USP22, is another validated anticancer target, being one of 11 genes in the death-from-cancer gene signature, a component of the human SAGA transcriptional cofactor complex regulating myc transcription, and a regulator of the expression of p21, the histone deacetylase Sirt 1, and p53 activity. USP22 is overexpressed in oral squamous cell carcinoma, breast, non-small cell lung, colorectal, and other cancers and its expression is inversely correlated with survival. Unlike most other DUBs, USP22 exhibits robust activity only as a component of a multi-subunit complex. Initial studies reported activity solely as a member of the 2MDa SAGA complex, but more recently it has been demonstrated that USP22 exhibits similar activity in a four-protein DUB module derived from the SAGA complex. USP22 inhibitors are expected to have broad anti-cancer activities. Progenra's UbiProTM discovery platform was utilized to screen ∼200K member diversity based library of small molecules for identifying novel USP22 inhibitors. Data will be presented describing these results. Citation Format: Feng Wang, Timothy R. Stanek, Leelabati Biswas, Matthew Kodrasov, James LaRocque, Jian Wu, David Sterner, Joseph Weinstock, Michael Mattern, Steven B. McMahon, Suresh Kumar. Discovery and characterization of USP22 inhibitors as novel anti-cancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5432. doi:10.1158/1538-7445.AM2015-5432