5 research outputs found
Identification and Characterization of Dual Inhibitors of the USP25/ 28 Deubiquitinating Enzyme Subfamily
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. Many USPs 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 DUB biology 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
Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors
Ubiquitin
specific protease 7 (USP7, HAUSP) has become an attractive
target in drug discovery due to the role it plays in modulating Mdm2
levels and consequently p53. Increasing interest in USP7 is emerging
due to its potential involvement in oncogenic pathways as well as
possible roles in both metabolic and immune disorders in addition
to viral infections. Potent, novel, and selective inhibitors of USP7
have been developed using both rational and structure-guided design
enabled by high-resolution cocrystallography. Initial hits were identified
via fragment-based screening, scaffold-hopping, and hybridization
exercises. Two distinct subseries are described along with associated
structure–activity relationship trends, as are initial efforts
aimed at developing compounds suitable for <i>in vivo</i> experiments. Overall, these discoveries will enable further research
into the wider biological role of USP7