Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites
Abstract
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family of enzymes, which catalyzes the removal of both 3'- and 5'-DNA phosphodiester adducts. Importantly, it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of human TOP1 and the 3'-phosphate of its DNA substrate. Blocking TDP1 function is an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. Previously, we reported the use of an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet, the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. We now report examining a 21 000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similar N,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke–Blackburn–Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structuresmore »
- Authors:
-
- National Cancer Institute, Frederick, MD (United States)
- National Cancer Institute, Bethesda, MD (United States)
- Frederick National Lab. for Cancer Research, Frederick, MD (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH); National Cancer Institute (NCI)
- OSTI Identifier:
- 1781727
- Grant/Contract Number:
- W-31-109-Eng-38; HHSN26120080001E; Z01-BC 006150; Z01-BC 006198
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Chemical Science
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 11; Journal ID: ISSN 2041-6520
- Publisher:
- Royal Society of Chemistry
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Zhao, Xue Zhi, Kiselev, Evgeny, Lountos, George T., Wang, Wenjie, Tropea, Joseph E., Needle, Danielle, Hilimire, Thomas A., Schneekloth, John S., Waugh, David S., Pommier, Yves, and Burke, Terrence R. Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites. United States: N. p., 2021.
Web. doi:10.1039/d0sc05411a.
Zhao, Xue Zhi, Kiselev, Evgeny, Lountos, George T., Wang, Wenjie, Tropea, Joseph E., Needle, Danielle, Hilimire, Thomas A., Schneekloth, John S., Waugh, David S., Pommier, Yves, & Burke, Terrence R. Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites. United States. https://doi.org/10.1039/d0sc05411a
Zhao, Xue Zhi, Kiselev, Evgeny, Lountos, George T., Wang, Wenjie, Tropea, Joseph E., Needle, Danielle, Hilimire, Thomas A., Schneekloth, John S., Waugh, David S., Pommier, Yves, and Burke, Terrence R. 2021.
"Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites". United States. https://doi.org/10.1039/d0sc05411a. https://www.osti.gov/servlets/purl/1781727.
@article{osti_1781727,
title = {Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites},
author = {Zhao, Xue Zhi and Kiselev, Evgeny and Lountos, George T. and Wang, Wenjie and Tropea, Joseph E. and Needle, Danielle and Hilimire, Thomas A. and Schneekloth, John S. and Waugh, David S. and Pommier, Yves and Burke, Terrence R.},
abstractNote = {Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family of enzymes, which catalyzes the removal of both 3'- and 5'-DNA phosphodiester adducts. Importantly, it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of human TOP1 and the 3'-phosphate of its DNA substrate. Blocking TDP1 function is an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. Previously, we reported the use of an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet, the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. We now report examining a 21 000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similar N,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke–Blackburn–Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site, while mimicking substrate interactions. Although our original fragment screen differed significantly from the current microarray protocol, both methods identified ligand–protein interactions containing highly similar elements. Importantly inhibitors identified through the SMM approach show competitive inhibition against TDP1 and access the catalytic phosphate-binding pocket, while simultaneously providing extensions into both the substrate DNA and peptide-binding channels. As such, they represent a platform for further elaboration of trivalent ligands, that could serve as a new genre of potent TDP1 inhibitors.},
doi = {10.1039/d0sc05411a},
url = {https://www.osti.gov/biblio/1781727},
journal = {Chemical Science},
issn = {2041-6520},
number = 11,
volume = 12,
place = {United States},
year = {Thu Jan 28 00:00:00 EST 2021},
month = {Thu Jan 28 00:00:00 EST 2021}
}
Works referenced in this record:
Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models
journal, January 2019
- Zakharenko, A. L.; Luzina, O. A.; Sokolov, D. N.
- European Journal of Medicinal Chemistry, Vol. 161
Debulking of topoisomerase DNA-protein crosslinks (TOP-DPC) by the proteasome, non-proteasomal and non-proteolytic pathways
journal, October 2020
- Sun, Yilun; Saha, Liton Kumar; Saha, Sourav
- DNA Repair, Vol. 94
Structural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1
journal, January 2018
- Flett, Fiona J.; Ruksenaite, Emilija; Armstrong, Lee A.
- Nature Communications, Vol. 9, Issue 1
Groebke–Blackburn–Bienaymé multicomponent reaction: emerging chemistry for drug discovery
journal, May 2015
- Shaaban, Saad; Abdel-Wahab, Bakr F.
- Molecular Diversity, Vol. 20, Issue 1
Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides
journal, August 2020
- Zakharenko, Alexandra L.; Drenichev, Mikhail S.; Dyrkheeva, Nadezhda S.
- Molecules, Vol. 25, Issue 16
The Groebke-Blackburn-Bienaymé Reaction: The Groebke-Blackburn-Bienaymé Reaction
journal, October 2019
- Boltjes, André; Dömling, Alexander
- European Journal of Organic Chemistry, Vol. 2019, Issue 42
Tyrosyl–DNA phosphodiesterases: rescuing the genome from the risks of relaxation
journal, December 2017
- Kawale, Ajinkya S.; Povirk, Lawrence F.
- Nucleic Acids Research, Vol. 46, Issue 2
Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential
journal, November 2016
- Laev, Sergey S.; Salakhutdinov, Nariman F.; Lavrik, Olga I.
- Bioorganic & Medicinal Chemistry, Vol. 24, Issue 21
Antimetastatic Activity of Combined Topotecan and Tyrosyl-DNA Phosphodiesterase-1 Inhibitor on Modeled Lewis Lung Carcinoma
journal, March 2019
- Koldysheva, E. V.; Men’shchikova, A. P.; Lushnikova, E. L.
- Bulletin of Experimental Biology and Medicine, Vol. 166, Issue 5
The Crystal Structure of Human Tyrosyl-DNA Phosphodiesterase, Tdp1
journal, February 2002
- Davies, Douglas R.; Interthal, Heidrun; Champoux, James J.
- Structure, Vol. 10, Issue 2
SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity
journal, May 2005
- Interthal, Heidrun; Chen, Hong Jing; Kehl-Fie, Thomas E.
- The EMBO Journal, Vol. 24, Issue 12
DNA Topoisomerase I Inhibitors: Chemistry, Biology, and Interfacial Inhibition
journal, May 2009
- Pommier, Yves
- Chemical Reviews, Vol. 109, Issue 7
Tyrosyl-DNA Phosphodiesterase 1 Targeting for Modulation of Camptothecin-Based Treatment
journal, May 2010
- Beretta, G.; Cossa, G.; Gatti, L.
- Current Medicinal Chemistry, Vol. 17, Issue 15
PAINS: Relevance to Tool Compound Discovery and Fragment-Based Screening
journal, January 2013
- Baell, Jonathan B.; Ferrins, Lori; Falk, Hendrik
- Australian Journal of Chemistry, Vol. 66, Issue 12
Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy
journal, December 2019
- Khomenko, Tatyana M.; Zakharenko, Alexandra L.; Chepanova, Arina A.
- International Journal of Molecular Sciences, Vol. 21, Issue 1
Multivalent ligand: design principle for targeted therapeutic delivery approach
journal, October 2012
- Chittasupho, Chuda
- Therapeutic Delivery, Vol. 3, Issue 10
Insights into Substrate Binding and Catalytic Mechanism of Human Tyrosyl-DNA Phosphodiesterase (Tdp1) from Vanadate and Tungstate-inhibited Structures
journal, December 2002
- Davies, Douglas R.; Interthal, Heidrun; Champoux, James J.
- Journal of Molecular Biology, Vol. 324, Issue 5
Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)
journal, July 2014
- Pommier, Yves; Huang, Shar-yin N.; Gao, Rui
- DNA Repair, Vol. 19
Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017—Utility and Limitations
journal, December 2017
- Baell, Jonathan B.; Nissink, J. Willem M.
- ACS Chemical Biology, Vol. 13, Issue 1
Crystal Structure of a Transition State Mimic for Tdp1 Assembled from Vanadate, DNA, and a Topoisomerase I-Derived Peptide
journal, February 2003
- Davies, Douglas R.; Interthal, Heidrun; Champoux, James J.
- Chemistry & Biology, Vol. 10, Issue 2
A Small-Molecule Microarray Approach for the Identification of E2 Enzyme Inhibitors in Ubiquitin-Like Conjugation Pathways
journal, July 2017
- Zlotkowski, Katherine; Hewitt, William M.; Sinniah, Ranu S.
- SLAS Discovery, Vol. 22, Issue 6
Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity
journal, March 2019
- Zakharenko, Alexandra; Dyrkheeva, Nadezhda; Lavrik, Olga
- Medicinal Research Reviews, Vol. 39, Issue 4
SynergyFinder 2.0: visual analytics of multi-drug combination synergies
journal, April 2020
- Ianevski, Aleksandr; Giri, Anil K.; Aittokallio, Tero
- Nucleic Acids Research, Vol. 48, Issue W1
Explorations of Peptide and Oligonucleotide Binding Sites of Tyrosyl-DNA Phosphodiesterase Using Vanadate Complexes
journal, February 2004
- Davies, Douglas R.; Interthal, Heidrun; Champoux, James J.
- Journal of Medicinal Chemistry, Vol. 47, Issue 4
A method for the covalent capture and screening of diverse small molecules in a microarray format
journal, December 2006
- Bradner, James E.; McPherson, Olivia M.; Koehler, Angela N.
- Nature Protocols, Vol. 1, Issue 5
Learning from PAINful lessons
journal, February 2015
- Erlanson, Daniel A.
- Journal of Medicinal Chemistry, Vol. 58, Issue 5
A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation
journal, November 2020
- Sun, Yilun; Miller Jenkins, Lisa M.; Su, Yijun P.
- Science Advances, Vol. 6, Issue 46
Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors
journal, July 2020
- Luzina, Olga; Filimonov, Alexander; Zakharenko, Alexandra
- Journal of Natural Products, Vol. 83, Issue 8
Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel
journal, January 2014
- Gao, Rui; Das, Benu Brata; Chatterjee, Raghunath
- DNA Repair, Vol. 13
Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening
journal, June 2019
- Lountos, George T.; Zhao, Xue Zhi; Kiselev, Evgeny
- Nucleic Acids Research, Vol. 47, Issue 19
Targeting Topoisomerase I in the Era of Precision Medicine
journal, June 2019
- Thomas, Anish; Pommier, Yves
- Clinical Cancer Research, Vol. 25, Issue 22
Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target
journal, October 2014
- Comeaux, Evan Q.; van Waardenburg, Robert C. A. M.
- Drug Metabolism Reviews, Vol. 46, Issue 4
TDP1 Overexpression in Human Cells Counteracts DNA Damage Mediated by Topoisomerases I and II
journal, December 2004
- Barthelmes, Hans U.; Habermeyer, Michael; Christensen, Morten O.
- Journal of Biological Chemistry, Vol. 279, Issue 53
Identification of Biologically Active, HIV TAR RNA-Binding Small Molecules Using Small Molecule Microarrays
journal, May 2014
- Sztuba-Solinska, Joanna; Shenoy, Shilpa R.; Gareiss, Peter
- Journal of the American Chemical Society, Vol. 136, Issue 23
Biochemical Assays for the Discovery of TDP1 Inhibitors
journal, July 2014
- Marchand, C.; Huang, S. -y. N.; Dexheimer, T. S.
- Molecular Cancer Therapeutics, Vol. 13, Issue 8
A pipeline for ligand discovery using small-molecule microarrays
journal, February 2007
- Duffner, Jay L.; Clemons, Paul A.; Koehler, Angela N.
- Current Opinion in Chemical Biology, Vol. 11, Issue 1
The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
journal, September 2020
- Gladkova, Elizaveta D.; Nechepurenko, Ivan V.; Bredikhin, Roman A.
- International Journal of Molecular Sciences, Vol. 21, Issue 19