Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme – ubiquitin complex

St-Cyr, Daniel; Ceccarelli, Derek F.; Orlicky, Stephen; van der Sloot, Almer M.; Tang, Xiaojing; Kelso, Susan; Moore, Susan; James, Clint; Posternak, Ganna; Coulombe-Huntington, Jasmin; Bertomeu, Thierry; Marinier, Anne; Sicheri, Frank; Tyers, Mike

doi:10.1126/sciadv.abi5797

Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme – ubiquitin complex

Journal Article · 01 October 2021 · Science Advances

DOI:https://doi.org/10.1126/sciadv.abi5797· OSTI ID:1844720

St-Cyr, Daniel; Ceccarelli, Derek F.; Orlicky, Stephen; van der Sloot, Almer M.; Tang, Xiaojing; Kelso, Susan; Moore, Susan; James, Clint; Posternak, Ganna; Coulombe-Huntington, Jasmin; Bertomeu, Thierry; Marinier, Anne; Sicheri, Frank; Tyers, Mike

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: DOE - Office Of Science; FOREIGN

OSTI ID:: 1844720

Journal Information:: Science Advances, Vol. 7, Issue 44; ISSN 2375-2548

Publisher:: AAAS

Country of Publication:: United States

Language:: ENGLISH

References (53)

Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development Dove, Katja K.; Kemp, Hilary A.; Di Bona, Kristin R. Proceedings of the National Academy of Sciences, Vol. 114, Issue 32 https://doi.org/10.1073/pnas.1705060114	journal	July 2017
Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki Nature Chemical Biology, Vol. 13, Issue 8 https://doi.org/10.1038/nchembio.2386	journal	June 2017
An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme Ceccarelli, Derek F.; Tang, Xiaojing; Pelletier, Benoit Cell, Vol. 145, Issue 7 https://doi.org/10.1016/j.cell.2011.05.039	journal	June 2011
E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin Huang, Hao; Ceccarelli, Derek F.; Orlicky, Stephen Nature Chemical Biology, Vol. 10, Issue 2 https://doi.org/10.1038/nchembio.1412	journal	December 2013
A Strategy for Modulation of Enzymes in the Ubiquitin System Ernst, Andreas; Avvakumov, George; Tong, Jiefei Science, Vol. 339, Issue 6119 https://doi.org/10.1126/science.1230161	journal	January 2013
Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism Cappadocia, Laurent; Lima, Christopher D. Chemical Reviews, Vol. 118, Issue 3 https://doi.org/10.1021/acs.chemrev.6b00737	journal	February 2017
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays Baell, Jonathan B.; Holloway, Georgina A. Journal of Medicinal Chemistry, Vol. 53, Issue 7 https://doi.org/10.1021/jm901137j	journal	April 2010
Ubiquitin Ligases: Structure, Function, and Regulation Zheng, Ning; Shabek, Nitzan Annual Review of Biochemistry, Vol. 86, Issue 1 https://doi.org/10.1146/annurev-biochem-060815-014922	journal	June 2017
SCF ubiquitin ligase-targeted therapies Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele Nature Reviews Drug Discovery, Vol. 13, Issue 12 https://doi.org/10.1038/nrd4432	journal	November 2014
E2 enzymes: more than just middle men Stewart, Mikaela D.; Ritterhoff, Tobias; Klevit, Rachel E. Cell Research, Vol. 26, Issue 4 https://doi.org/10.1038/cr.2016.35	journal	March 2016
Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions Sijbesma, Eline; Visser, Emira; Plitzko, Kathrin Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-17741-0	journal	August 2020
Mechanisms and function of substrate recruitment by F-box proteins Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele Nature Reviews Molecular Cell Biology, Vol. 14, Issue 6 https://doi.org/10.1038/nrm3582	journal	May 2013
Modes of allosteric regulation of the ubiquitination machinery Rennie, Martin L.; Chaugule, Viduth K.; Walden, Helen Current Opinion in Structural Biology, Vol. 62 https://doi.org/10.1016/j.sbi.2020.02.003	journal	June 2020
Induced protein degradation: an emerging drug discovery paradigm Lai, Ashton C.; Crews, Craig M. Nature Reviews Drug Discovery, Vol. 16, Issue 2 https://doi.org/10.1038/nrd.2016.211	journal	November 2016
Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field Krieger, Elmar; Koraimann, Günther; Vriend, Gert Proteins: Structure, Function, and Bioinformatics, Vol. 47, Issue 3 https://doi.org/10.1002/prot.10104	journal	May 2002
The Rise of Molecular Glues Schreiber, Stuart L. Cell, Vol. 184, Issue 1 https://doi.org/10.1016/j.cell.2020.12.020	journal	January 2021
SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules Daina, Antoine; Michielin, Olivier; Zoete, Vincent Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep42717	journal	March 2017
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation Jakalian, Araz; Jack, David B.; Bayly, Christopher I. Journal of Computational Chemistry, Vol. 23, Issue 16 https://doi.org/10.1002/jcc.10128	journal	October 2002
N-degron and C-degron pathways of protein degradation Varshavsky, Alexander Proceedings of the National Academy of Sciences, Vol. 116, Issue 2 https://doi.org/10.1073/pnas.1816596116	journal	January 2019
The F-box protein TIR1 is an auxin receptor Dharmasiri, Nihal; Dharmasiri, Sunethra; Estelle, Mark Nature, Vol. 435, Issue 7041 https://doi.org/10.1038/nature03543	journal	May 2005
Essential Role for Ubiquitin-Ubiquitin-Conjugating Enzyme Interaction in Ubiquitin Discharge from Cdc34 to Substrate Saha, Anjanabha; Lewis, Steven; Kleiger, Gary Molecular Cell, Vol. 42, Issue 1 https://doi.org/10.1016/j.molcel.2011.03.016	journal	April 2011
E1 Enzymes as Therapeutic Targets in Cancer Barghout, Samir H.; Schimmer, Aaron D. Pharmacological Reviews, Vol. 73, Issue 1 https://doi.org/10.1124/pharmrev.120.000053	journal	November 2020
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction Simonetta, Kyle R.; Taygerly, Joshua; Boyle, Kathleen Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09358-9	journal	March 2019
Cereblon modulators: Low molecular weight inducers of protein degradation Chamberlain, Philip P.; Cathers, Brian E. Drug Discovery Today: Technologies, Vol. 31 https://doi.org/10.1016/j.ddtec.2019.02.004	journal	April 2019
Drug Discovery Applications for KNIME: An Open Source Data Mining Platform P. Mazanetz, Michael; J. Marmon, Robert; B. T. Reisser, Catherine Current Topics in Medicinal Chemistry, Vol. 12, Issue 18 https://doi.org/10.2174/156802612804910331	journal	September 2012
Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation Scott, Daniel C.; Rhee, David Y.; Duda, David M. Cell, Vol. 166, Issue 5 https://doi.org/10.1016/j.cell.2016.07.027	journal	August 2016
Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives Chen, Hao; Wu, Guozhen; Gao, Shuang Journal of Medicinal Chemistry, Vol. 60, Issue 16 https://doi.org/10.1021/acs.jmedchem.6b01829	journal	August 2017
Building and remodelling Cullin–RING E3 ubiquitin ligases Lydeard, John R.; Schulman, Brenda A.; Harper, J. Wade EMBO reports, Vol. 14, Issue 12 https://doi.org/10.1038/embor.2013.173	journal	November 2013
Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9 Hewitt, William M.; Lountos, George T.; Zlotkowski, Katherine Angewandte Chemie International Edition, Vol. 55, Issue 19 https://doi.org/10.1002/anie.201511351	journal	April 2016
An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase Orlicky, Stephen; Tang, Xiaojing; Neduva, Victor Nature Biotechnology, Vol. 28, Issue 7 https://doi.org/10.1038/nbt.1646	journal	June 2010
Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities Davis, Ryan J.; Welcker, Markus; Clurman, Bruce E. Cancer Cell, Vol. 26, Issue 4 https://doi.org/10.1016/j.ccell.2014.09.013	journal	October 2014
Inducing protein-protein interactions with molecular glues Che, Ye; Gilbert, Adam M.; Shanmugasundaram, Veerabahu Bioorganic & Medicinal Chemistry Letters, Vol. 28, Issue 15 https://doi.org/10.1016/j.bmcl.2018.04.046	journal	August 2018
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
Cloning and expression of the human augmenter of liver regeneration at low temperature in Escherichia coli Sheng, Jifang; Yu, Haiying; Li, Jun Journal of Biochemical and Biophysical Methods, Vol. 70, Issue 3 https://doi.org/10.1016/j.jbbm.2006.11.009	journal	April 2007
Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies Lucas, Xavier; Ciulli, Alessio Current Opinion in Structural Biology, Vol. 44 https://doi.org/10.1016/j.sbi.2016.12.015	journal	June 2017
Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34 Seol, J. H.; Feldman, R. M. R.; Zachariae, W. Genes & Development, Vol. 13, Issue 12 https://doi.org/10.1101/gad.13.12.1614	journal	June 1999
Stabilization of protein-protein interactions in drug discovery Andrei, Sebastian A.; Sijbesma, Eline; Hann, Michael Expert Opinion on Drug Discovery, Vol. 12, Issue 9 https://doi.org/10.1080/17460441.2017.1346608	journal	July 2017
Ubiquitylation at the crossroads of development and disease Rape, Michael Nature Reviews Molecular Cell Biology, Vol. 19, Issue 1 https://doi.org/10.1038/nrm.2017.83	journal	September 2017
Potent 5-Cyano-6-phenyl-pyrimidin-Based Derivatives Targeting DCN1–UBE2M Interaction Zhou, Wenjuan; Ma, Liying; Ding, Lina Journal of Medicinal Chemistry, Vol. 62, Issue 11 https://doi.org/10.1021/acs.jmedchem.9b00003	journal	May 2019
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins Lu, G.; Middleton, R. E.; Sun, H. Science, Vol. 343, Issue 6168 https://doi.org/10.1126/science.1244917	journal	November 2013
The increasing complexity of the ubiquitin code Yau, Richard; Rape, Michael Nature Cell Biology, Vol. 18, Issue 6 https://doi.org/10.1038/ncb3358	journal	May 2016
Targeted protein degradation as a powerful research tool in basic biology and drug target discovery Wu, Tao; Yoon, Hojong; Xiong, Yuan Nature Structural & Molecular Biology, Vol. 27, Issue 7 https://doi.org/10.1038/s41594-020-0438-0	journal	June 2020
NEDD8 and ubiquitin ligation by cullin-RING E3 ligases Baek, Kheewoong; Scott, Daniel C.; Schulman, Brenda A. Current Opinion in Structural Biology, Vol. 67 https://doi.org/10.1016/j.sbi.2020.10.007	journal	April 2021
Small molecules, big targets: drug discovery faces the protein–protein interaction challenge Scott, Duncan E.; Bayly, Andrew R.; Abell, Chris Nature Reviews Drug Discovery, Vol. 15, Issue 8 https://doi.org/10.1038/nrd.2016.29	journal	April 2016
Clinical Overview of MDM2/X-Targeted Therapies Burgess, Andrew; Chia, Kee Ming; Haupt, Sue Frontiers in Oncology, Vol. 6 https://doi.org/10.3389/fonc.2016.00007	journal	January 2016
The Mechanism of Linkage-Specific Ubiquitin Chain Elongation by a Single-Subunit E2 Wickliffe, Katherine E.; Lorenz, Sonja; Wemmer, David E. Cell, Vol. 144, Issue 5 https://doi.org/10.1016/j.cell.2011.01.035	journal	March 2011
Allosteric Targeting of the Fanconi Anemia Ubiquitin-Conjugating Enzyme Ube2T by Fragment Screening Morreale, Francesca E.; Bortoluzzi, Alessio; Chaugule, Viduth K. Journal of Medicinal Chemistry, Vol. 60, Issue 9 https://doi.org/10.1021/acs.jmedchem.7b00147	journal	May 2017
Rapid E2-E3 Assembly and Disassembly Enable Processive Ubiquitylation of Cullin-RING Ubiquitin Ligase Substrates Kleiger, Gary; Saha, Anjanabha; Lewis, Steven Cell, Vol. 139, Issue 5 https://doi.org/10.1016/j.cell.2009.10.030	journal	November 2009
MOPAC: A semiempirical molecular orbital program Stewart, James J. P. Journal of Computer-Aided Molecular Design, Vol. 4, Issue 1 https://doi.org/10.1007/BF00128336	journal	March 1990
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
RING Domain E3 Ubiquitin Ligases Deshaies, Raymond J.; Joazeiro, Claudio A. P. Annual Review of Biochemistry, Vol. 78, Issue 1 https://doi.org/10.1146/annurev.biochem.78.101807.093809	journal	June 2009
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways Hill, Spencer; Reichermeier, Kurt; Scott, Daniel C. eLife, Vol. 8 https://doi.org/10.7554/eLife.51163	journal	December 2019

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