Abstract 3207: Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14

Abstract

Abstract The 20S proteasome core particle has evolved as an important target for anti-cancer drug development. We previously identified the small molecule b-AP15 as a novel class of proteasome inhibitors that function by abrogating the deubiquitinating (DUB) activity of the 19S regulatory particle. An optimised lead of b-AP15 (VLX1570) has been approved by the FDA for clinical studies and is currently in clinical trials for relapsed multiple myeloma. VLX1570 has also shown promising activity in Ewings sarcoma and paediatric leukemias. b-AP15 and VLX1570 bind to the proteasome DUB ubiquitin-specific protease-14 (USP14) in vitro and in exposed cells (CETSA). Binding and inhibition of enzymatic activity is believed to be due to targeting Cys114 in the active site. The cell death response to b-AP15/VLX1570 is distinct from that of 20S proteasome inhibitors. Thus, the sensitivity to these compounds is unaffected by overexpression of BCL2-family proteins and unaffected by p53 status. We here show that b-AP15 induces direct effects on mitochondria, possible explaining this phenomenon. We also provide additional understanding of drug-target interactions using a series of compounds identified by screening. Our findings demonstrate promising antiproliferative activities of USP14 inhibitors in vitro and in vivo. Citation Format: Stig T. Linder, Padraig D'Arcy, Xiaonan Zhang. Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3207. doi:10.1158/1538-7445.AM2017-3207