Identification
of 1,2,5-Oxadiazoles as a New Class
of SENP2 Inhibitors Using Structure Based Virtual Screening
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Abstract
Small ubiquitin like modifier (SUMO)
specific proteases (SENPs)
are cysteine proteases that carry out the proteolytic processing of
SUMO from its pro form as well as the deconjugation of SUMO from substrate
proteins. SENPs are attractive targets for drug discovery due to their
crucial role in the development of various diseases. However, the
SENPs inhibitor discovery efforts were limited, and only a few inhibitors
or activity based probes have been identified until now. Here, we
report a new class of SENP2 inhibitors identified by a combination
of structure based virtual screening and quantitative FRET based assay.
Our virtual screening protocol initially involves the identification
of small molecules that have similar shape and electrostatic properties
with the conjugate of SUMO1 C-terminal residues and substrate lysine.
Molecular docking was then used to prioritize these small molecules
for a FRET based assay that quantifies their SENP2 endopeptidase activity.
The initial round of virtual screening followed by FRET based assay
has enabled the identification of eight compounds with >40% SENP2
inhibition at 30 μM compound concentration. Five of these compounds
belong to two scaffolds containing a 1,2,5-oxadiazole core that represent
a novel class of SENP2 inhibitors. To improve the inhibitory potency
and explore the structure–activity relationship of these two
1,2,5-oxadiazole scaffolds, structurally related compounds were identified
in another round of virtual screening. The biological assay results
confirmed SENP2 inhibitory activity of these two scaffolds. The most
potent compound of each scaffold showed an IC<sub>50</sub> of 5.9
and 3.7 μM. Most of the compounds also inhibited closely related
isoform SENP1, while no detectable inhibition on other proteases,
such as papain and trypsin, was observed. Our study suggests that
1,2,5-oxadiazoles could be used as a starting point for the development
of novel therapeutic agents against various diseases targeting SENPs
