10.1021/acschembio.7b00020.s003
Allison
M. Roberts
Allison
M.
Roberts
David K. Miyamoto
David K.
Miyamoto
Tucker R. Huffman
Tucker R.
Huffman
Leslie A. Bateman
Leslie A.
Bateman
Ashley N. Ives
Ashley N.
Ives
David Akopian
David
Akopian
Martin J. Heslin
Martin J.
Heslin
Carlo M. Contreras
Carlo M.
Contreras
Michael Rape
Michael
Rape
Christine F. Skibola
Christine
F. Skibola
Daniel K. Nomura
Daniel K.
Nomura
Chemoproteomic Screening of Covalent Ligands Reveals
UBA5 As a Novel Pancreatic Cancer Target
American Chemical Society
2017
DKM
platform
screening
covalent ligand libraries
compound
pancreatic cancer pathogenicity
Novel Pancreatic Cancer Target Chemical
cysteine-reactive fragment-based covalent ligand library
isoTOP-ABPP
UBA 5
impairs pancreatic cancer cell survival
druggable hotspots
tandem orthogonal proteolysis-enabled activity-based protein
vivo tumor growth
ubiquitin-like protein UFM 1
molecule
novel pancreatic cancer
cancer therapy
2017-02-10 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/Chemoproteomic_Screening_of_Covalent_Ligands_Reveals_UBA5_As_a_Novel_Pancreatic_Cancer_Target/4654627
Chemical genetic screening of small-molecule
libraries has been a promising strategy for discovering unique and
novel therapeutic compounds. However, identifying the targets of lead
molecules that arise from these screens has remained a major bottleneck
in understanding the mechanism of action of these compounds. Here,
we have coupled the screening of a cysteine-reactive fragment-based
covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled
activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform
to rapidly couple the discovery of lead small molecules that impair
pancreatic cancer pathogenicity with the identification of druggable
hotspots for potential cancer therapy. Through this coupled approach,
we have discovered a covalent ligand DKM 2–93 that impairs
pancreatic cancer cell survival and <i>in vivo</i> tumor
growth through covalently modifying the catalytic cysteine of the
ubiquitin-like modifier activating enzyme 5 (UBA5), thereby inhibiting
its activity as a protein that activates the ubiquitin-like protein
UFM1 to UFMylate proteins. We show that UBA5 is a novel pancreatic
cancer therapeutic target and show DKM 2–93 as a relatively
selective lead inhibitor of UBA5. Our results underscore the utility
of coupling the screening of covalent ligand libraries with isoTOP-ABPP
platforms for mining the proteome for druggable hotspots for cancer
therapy.