Deubiquitinating enzymes, or DUBs, comprise a family
of proteases
that regulate ubiquitination dynamics. Since their discovery, genetic
and functional studies have nominated DUBs as a promising class for
drug discovery across diverse therapeutic areas. Consequent probe
and drug discovery efforts over the past 15 years have resulted in
over 50 reported inhibitors and advances in DUB structural studies,
assay formats, and chemical biology tools. Accumulating knowledge
from these studies has enabled several important recent breakthroughs.
In this review, we highlight recent successes in solving DUB-ligand
co-structures and the development of rigorously characterized potent
and selective inhibitors. We posit that these advances in pharmacological
targeting of DUBs establish the enzyme family as targetable and provide
a framework for other DUBs programs. Accordingly, we envision increasingly
rapid progress in the development of potent and selective inhibitors
for a wide range of DUBs and advancement of DUB-targeting drugs to
the clinic.
Highlights d Most cancer cell lines are largely insensitive to GSH depletion d Deubiquitinases (DUBs) protect cancer cells upon inhibition of GSH synthesis d Inhibition of DUBs and GSH synthesis causes ER and proteotoxic stress and cell death d Combined targeting of DUBs and GSH blocks tumor growth
Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
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