TY - JOUR
T1 - Identification and Characterization of Dual Inhibitors of the USP25/ 28 Deubiquitinating Enzyme Subfamily
AU - Wrigley, Jonathon D.
AU - Gavory, Gerald
AU - Simpson, Iain
AU - Preston, Marian
AU - Plant, Helen
AU - Bradley, Jenna
AU - Goeppert, Anne U.
AU - Rozycka, Ewelina
AU - Davies, Gareth
AU - Walsh, Jarrod
AU - Valentine, Andrea
AU - McClelland, Keeva
AU - Odrzywol, Krzysztofa Ewa
AU - Renshaw, Jonathan
AU - Boros, Joanna
AU - Tart, Jonathan
AU - Leach, Lindsey
AU - Nowak, Thorsten
AU - Ward, Richard A.
AU - Harrison, Timothy
AU - Andrews, David M.
PY - 2017/11/13
Y1 - 2017/11/13
N2 - The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. ManyUSPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUBbiology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.
AB - The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. ManyUSPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUBbiology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.
U2 - 10.1021/acschembio.7b00334
DO - 10.1021/acschembio.7b00334
M3 - Article
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
ER -