A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1

Das, Debanu; Duncton, Matthew A. J.; Georgiadis, Taxiarchis M.; Pellicena, Patricia; Clark, Jennifer; Sobol, Robert W.; Georgiadis, Millie M.; King-Underwood, John; Jobes, David V.; Chang, Caleb; Gao, Yang; Deacon, Ashley M.; Wilson, III, David M.

doi:10.3390/ijms242316637

A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1

Journal Article · Wed Nov 22 23:00:00 EST 2023 · International Journal of Molecular Sciences (Online)

DOI:https://doi.org/10.3390/ijms242316637· OSTI ID:2471709

Das, Debanu ^[1]; ^[2]; Georgiadis, Taxiarchis M. ^[2]; ^[2]; Clark, Jennifer ^[3]; ^[4]; Georgiadis, Millie M. ^[5]; King-Underwood, John ^[2]; Jobes, David V. ^[6]; Chang, Caleb ^[7]; ^[7]; Deacon, Ashley M. ^[1]; Wilson, III, David M. ^[8]

XPose Therapeutics, Inc., San Carlos, CA (United States); Accelero Biostructures, Inc., San Carlos, CA (United States)
XPose Therapeutics, Inc., San Carlos, CA (United States)
University of South Alabama, Mobile, AL (United States)
University of South Alabama, Mobile, AL (United States); Brown University, Providence, RI (United States)
XPose Therapeutics, Inc., San Carlos, CA (United States); Indiana University School of Medicine, Indianapolis, IN (United States)
XPose Therapeutics, Inc., San Carlos, CA (United States); Mid-Atlantic BioTherapeutics, Inc., Doylestown, PA (United States)
Rice University, Houston, TX (United States)
XPose Therapeutics, Inc., San Carlos, CA (United States); Hasselt University, Diepenbeek (Belgium); Belgium & Boost Scientific, Heusden-Zolder (Belgium)

The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM (“SAR by X-ray Poses Quickly”) platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or “undruggable” targets, allows for (i) hit generation; (ii) the mapping of protein–ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol η or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2471709

Journal Information:: International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 23 Vol. 24; ISSN 1422-0067

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

References (100)

Design and Synthesis of 3-Carbamoylbenzoic Acid Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1) Aiello, Francesca; Shabaik, Yumna; Esqueda, Adrian ChemMedChem, Vol. 7, Issue 10 https://doi.org/10.1002/cmdc.201200334	journal	September 2012
Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors Sultana, Rebeka; McNeill, Daniel R.; Abbotts, Rachel International Journal of Cancer, Vol. 131, Issue 10 https://doi.org/10.1002/ijc.27512	journal	March 2012
DNA polymerase eta: A potential pharmacological target for cancer therapy Saha, Priyanka; Mandal, Tanima; Talukdar, Anupam D. Journal of Cellular Physiology, Vol. 236, Issue 6 https://doi.org/10.1002/jcp.30155	journal	November 2020
RCSB Protein Data Bank: Enabling biomedical research and drug discovery Goodsell, David S.; Zardecki, Christine; Di Costanzo, Luigi Protein Science, Vol. 29, Issue 1 https://doi.org/10.1002/pro.3730	journal	November 2019
Small molecule inhibitors of DNA repair nuclease activities of APE1 Wilson, David M.; Simeonov, Anton Cellular and Molecular Life Sciences, Vol. 67, Issue 21 https://doi.org/10.1007/s00018-010-0488-2	journal	August 2010
DNA glycosylases: in DNA repair and beyond Jacobs, Angelika L.; Schär, Primo Chromosoma, Vol. 121, Issue 1 https://doi.org/10.1007/s00412-011-0347-4	journal	November 2011
The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA Wilson, David M.; Barsky, Daniel Mutation Research/DNA Repair, Vol. 485, Issue 4 https://doi.org/10.1016/S0921-8777(01)00063-5	journal	May 2001
Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) Laev, Sergey S.; Salakhutdinov, Nariman F.; Lavrik, Olga I. Bioorganic & Medicinal Chemistry, Vol. 25, Issue 9 https://doi.org/10.1016/j.bmc.2017.01.028	journal	May 2017
Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies Grädler, Ulrich; Schwarz, Daniel; Blaesse, Michael Bioorganic & Medicinal Chemistry Letters, Vol. 29, Issue 23 https://doi.org/10.1016/j.bmcl.2019.126717	journal	December 2019
Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment Wheeler, David A.; Takebe, Naoko; Hinoue, Toshinori Cancer Cell, Vol. 39, Issue 1 https://doi.org/10.1016/j.ccell.2020.10.015	journal	January 2021
Hallmarks of Cancer: The Next Generation Hanahan, Douglas; Weinberg, Robert A. Cell, Vol. 144, Issue 5 https://doi.org/10.1016/j.cell.2011.02.013	journal	March 2011
Progress towards a clinically-successful ATR inhibitor for cancer therapy Barnieh, Francis M.; Loadman, Paul M.; Falconer, Robert A. Current Research in Pharmacology and Drug Discovery, Vol. 2 https://doi.org/10.1016/j.crphar.2021.100017	journal	January 2021
Abasic sites in DNA: repair and biological consequences in Saccharomyces cerevisiae Boiteux, Serge; Guillet, Marie DNA Repair, Vol. 3, Issue 1 https://doi.org/10.1016/j.dnarep.2003.10.002	journal	January 2004
Knockdown of the DNA repair and redox signaling protein Ape1/Ref-1 blocks ovarian cancer cell and tumor growth Fishel, Melissa L.; He, Ying; Reed, April M. DNA Repair, Vol. 7, Issue 2 https://doi.org/10.1016/j.dnarep.2007.09.008	journal	February 2008
Fragment-based drug discovery using cryo-EM Saur, Michael; Hartshorn, Michael J.; Dong, Jing Drug Discovery Today, Vol. 25, Issue 3 https://doi.org/10.1016/j.drudis.2019.12.006	journal	March 2020
The multifunctional APE1 DNA repair–redox signaling protein as a drug target in human disease Caston, Rachel A.; Gampala, Silpa; Armstrong, Lee Drug Discovery Today, Vol. 26, Issue 1 https://doi.org/10.1016/j.drudis.2020.10.015	journal	January 2021
Computer-aided identification, synthesis, and biological evaluation of DNA polymerase η inhibitors for the treatment of cancer Munafò, Federico; Nigro, Michela; Brindani, Nicoletta European Journal of Medicinal Chemistry, Vol. 248 https://doi.org/10.1016/j.ejmech.2022.115044	journal	February 2023
Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks Chakraborty, Anirban; Tapryal, Nisha; Islam, Azharul Journal of Biological Chemistry, Vol. 299, Issue 3 https://doi.org/10.1016/j.jbc.2023.102991	journal	March 2023
A Vital Role for Ape1/Ref1 Protein in Repairing Spontaneous DNA Damage in Human Cells Fung, Hua; Demple, Bruce Molecular Cell, Vol. 17, Issue 3 https://doi.org/10.1016/j.molcel.2004.12.029	journal	February 2005
Targeting the DNA Damage Response in Cancer O’Connor, Mark J. Molecular Cell, Vol. 60, Issue 4 https://doi.org/10.1016/j.molcel.2015.10.040	journal	November 2015
Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets Mengwasser, Kristen E.; Adeyemi, Richard O.; Leng, Yumei Molecular Cell, Vol. 73, Issue 5 https://doi.org/10.1016/j.molcel.2018.12.008	journal	March 2019
The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining Fleury, Hubert; MacEachern, Myles K.; Stiefel, Clara M. Molecular Cell, Vol. 83, Issue 9 https://doi.org/10.1016/j.molcel.2023.03.017	journal	May 2023
DNA repair inhibition: a selective tumour targeting strategy Madhusudan, Srinivasan; Hickson, Ian D. Trends in Molecular Medicine, Vol. 11, Issue 11 https://doi.org/10.1016/j.molmed.2005.09.004	journal	November 2005
APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line Montaldi, Ana P.; Godoy, Paulo R. D. V.; Sakamoto-Hojo, Elza T. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 793 https://doi.org/10.1016/j.mrgentox.2015.06.001	journal	November 2015
DNA polymerase eta protects human cells against DNA damage induced by the tumor chemotherapeutic temozolomide Latancia, Marcela T.; Moreno, Natália C.; Leandro, Giovana S. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 878 https://doi.org/10.1016/j.mrgentox.2022.503498	journal	June 2022
Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response Wilson, David M.; Deacon, Ashley M.; Duncton, Matthew A. J. Progress in Biophysics and Molecular Biology https://doi.org/10.1016/j.pbiomolbio.2020.10.005	journal	October 2020
NMR in drug discovery: A practical guide to identification and validation of ligands interacting with biological macromolecules Gossert, Alvar D.; Jahnke, Wolfgang Progress in Nuclear Magnetic Resonance Spectroscopy, Vol. 97 https://doi.org/10.1016/j.pnmrs.2016.09.001	journal	November 2016
A Small-Molecule Inhibitor of Human DNA Polymerase η Potentiates the Effects of Cisplatin in Tumor Cells Zafar, Maroof K.; Maddukuri, Leena; Ketkar, Amit Biochemistry, Vol. 57, Issue 7 https://doi.org/10.1021/acs.biochem.7b01176	journal	January 2018
Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors Sabbah, Mohamad; Mendes, Vitor; Vistal, Robert G. Journal of Medicinal Chemistry, Vol. 63, Issue 9 https://doi.org/10.1021/acs.jmedchem.0c00007	journal	April 2020
Discovery of WD Repeat-Containing Protein 5 (WDR5)–MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design Chacón Simon, Selena; Wang, Feng; Thomas, Lance R. Journal of Medicinal Chemistry, Vol. 63, Issue 8 https://doi.org/10.1021/acs.jmedchem.0c00224	journal	March 2020
Efficient Translesion Replication Past Oxaliplatin and Cisplatin GpG Adducts by Human DNA Polymerase η ^† Vaisman, Alexandra; Masutani, Chikahide; Hanaoka, Fumio Biochemistry, Vol. 39, Issue 16 https://doi.org/10.1021/bi000130k	journal	April 2000
Rate of depurination of native deoxyribonucleic acid Lindahl, Tomas; Nyberg, Barbro Biochemistry, Vol. 11, Issue 19 https://doi.org/10.1021/bi00769a018	journal	September 1972
An Overview of Y-Family DNA Polymerases and a Case Study of Human DNA Polymerase η Yang, Wei Biochemistry, Vol. 53, Issue 17 https://doi.org/10.1021/bi500019s	journal	April 2014
High-Resolution Crystal Structures Reveal Plasticity in the Metal Binding Site of Apurinic/Apyrimidinic Endonuclease I He, Hongzhen; Chen, Qiujia; Georgiadis, Millie M. Biochemistry, Vol. 53, Issue 41 https://doi.org/10.1021/bi500676p	journal	October 2014
N-Aroyl Indole Thiobarbituric Acids as Inhibitors of DNA Repair and Replication Stress Response Polymerases Coggins, Grace E.; Maddukuri, Leena; Penthala, Narsima R. ACS Chemical Biology, Vol. 8, Issue 8 https://doi.org/10.1021/cb400305r	journal	May 2013
Synthesis, Biological Evaluation, and Structure–Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors Rai, Ganesha; Vyjayanti, Vaddadi N.; Dorjsuren, Dorjbal Journal of Medicinal Chemistry, Vol. 55, Issue 7 https://doi.org/10.1021/jm201537d	journal	March 2012
Pharmacophore Guided Discovery of Small-Molecule Human Apurinic/Apyrimidinic Endonuclease 1 Inhibitors Zawahir, Zahrah; Dayam, Raveendra; Deng, Jinxia Journal of Medicinal Chemistry, Vol. 52, Issue 1 https://doi.org/10.1021/jm800739m	journal	December 2008
Fragment Screening by Surface Plasmon Resonance Navratilova, Iva; Hopkins, Andrew L. ACS Medicinal Chemistry Letters, Vol. 1, Issue 1 https://doi.org/10.1021/ml900002k	journal	January 2010
DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination Mol, Clifford D.; Izumi, Tadahide; Mitra, Sankar Nature, Vol. 403, Issue 6768 https://doi.org/10.1038/35000249	journal	January 2000
Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair Li, Xiao-qin; Ren, Jin; Chen, Ping Acta Pharmacologica Sinica, Vol. 39, Issue 8 https://doi.org/10.1038/aps.2017.187	journal	May 2018
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase Bryant, Helen E.; Schultz, Niklas; Thomas, Huw D. Nature, Vol. 434, Issue 7035 https://doi.org/10.1038/nature03443	journal	April 2005
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Farmer, Hannah; McCabe, Nuala; Lord, Christopher J. Nature, Vol. 434, Issue 7035 https://doi.org/10.1038/nature03445	journal	April 2005
The DNA-damage response in human biology and disease Jackson, Stephen P.; Bartek, Jiri Nature, Vol. 461, Issue 7267 https://doi.org/10.1038/nature08467	journal	October 2009
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets Souers, Andrew J.; Leverson, Joel D.; Boghaert, Erwin R. Nature Medicine, Vol. 19, Issue 2 https://doi.org/10.1038/nm.3048	journal	January 2013
DNA repair pathways as targets for cancer therapy Helleday, Thomas; Petermann, Eva; Lundin, Cecilia Nature Reviews Cancer, Vol. 8, Issue 3 https://doi.org/10.1038/nrc2342	journal	March 2008
Vemurafenib: the first drug approved for BRAF-mutant cancer Bollag, Gideon; Tsai, James; Zhang, Jiazhong Nature Reviews Drug Discovery, Vol. 11, Issue 11 https://doi.org/10.1038/nrd3847	journal	October 2012
Functional screening reveals HORMAD1-driven gene dependencies associated with translesion synthesis and replication stress tolerance Tarantino, Dalia; Walker, Callum; Weekes, Daniel Oncogene, Vol. 41, Issue 32 https://doi.org/10.1038/s41388-022-02369-9	journal	June 2022
Next generation high throughput DNA damage detection platform for genotoxic compound screening Sykora, Peter; Witt, Kristine L.; Revanna, Pooja Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-20995-w	journal	February 2018
Design of amino acid- and carbohydrate-based anticancer drugs to inhibit polymerase η Kalhor, Sepideh; Fattahi, Alireza Scientific Reports, Vol. 12, Issue 1 https://doi.org/10.1038/s41598-022-22810-z	journal	November 2022
Base excision repair and its implications to cancer therapy Grundy, Gabrielle J.; Parsons, Jason L. Essays in Biochemistry, Vol. 64, Issue 5 https://doi.org/10.1042/EBC20200013	journal	July 2020
Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor Tap, William D.; Wainberg, Zev A.; Anthony, Stephen P. New England Journal of Medicine, Vol. 373, Issue 5 https://doi.org/10.1056/NEJMoa1411366	journal	July 2015
Two essential but distinct functions of the mammalian abasic endonuclease Izumi, T.; Brown, D. B.; Naidu, C. V. Proceedings of the National Academy of Sciences, Vol. 102, Issue 16 https://doi.org/10.1073/pnas.0500986102	journal	April 2005
Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells Srivastava, Amit Kumar; Han, Chunhua; Zhao, Ran Proceedings of the National Academy of Sciences, Vol. 112, Issue 14 https://doi.org/10.1073/pnas.1421365112	journal	March 2015
Bypassing a 8,5′-cyclo-2′-deoxyadenosine lesion by human DNA polymerase η at atomic resolution Weng, Peter J.; Gao, Yang; Gregory, Mark T. Proceedings of the National Academy of Sciences, Vol. 115, Issue 42 https://doi.org/10.1073/pnas.1812856115	journal	October 2018
Oxygen Free Radical Damage to DNA Kuraoka, Isao; Robins, Peter; Masutani, Chikahide Journal of Biological Chemistry, Vol. 276, Issue 52 https://doi.org/10.1074/jbc.M107779200	journal	December 2001
Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyrimidinic Endonuclease APE1 and Endonuclease IV DNA Repair Enzymes Tsutakawa, Susan E.; Shin, David S.; Mol, Clifford D. Journal of Biological Chemistry, Vol. 288, Issue 12 https://doi.org/10.1074/jbc.M112.422774	journal	January 2013
Translesion synthesis DNA polymerases η, ι, and ν promote mutagenic replication through the anticancer nucleoside cytarabine Yoon, Jung-Hoon; Roy Choudhury, Jayati; Prakash, Louise Journal of Biological Chemistry, Vol. 294, Issue 50 https://doi.org/10.1074/jbc.RA119.011381	journal	December 2019
Human Apurinic/Apyrimidinic Endonuclease 1 Li, Mengxia; Wilson, David M. Antioxidants & Redox Signaling, Vol. 20, Issue 4 https://doi.org/10.1089/ars.2013.5492	journal	February 2014
Functions of the major abasic endonuclease (APE1) in cell viability and genotoxin resistance McNeill, Daniel R.; Whitaker, Amy M.; Stark, Wesley J. Mutagenesis, Vol. 35, Issue 1 https://doi.org/10.1093/mutage/gez046	journal	December 2019
A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress Walker, Lisa J.; Craig, Randa B.; Harris, Adrian L. Nucleic Acids Research, Vol. 22, Issue 23 https://doi.org/10.1093/nar/22.23.4884	journal	January 1994
Genetic vulnerabilities upon inhibition of DNA damage response Wang, Chao; Tang, Mengfan; Chen, Zhen Nucleic Acids Research, Vol. 49, Issue 14 https://doi.org/10.1093/nar/gkab643	journal	July 2021
Isolation of a small molecule inhibitor of DNA base excision repair Madhusudan, S.; Smart, F.; Shrimpton, P. Nucleic Acids Research, Vol. 33, Issue 15 https://doi.org/10.1093/nar/gki781	journal	August 2005
APE2: catalytic function and synthetic lethality draw attention as a cancer therapy target McMahon, Anne; Zhao, Jianjun; Yan, Shan NAR Cancer, Vol. 5, Issue 1 https://doi.org/10.1093/narcan/zcad006	journal	January 2023
N-methylpurine DNA glycosylase and DNA polymerase β modulate BER inhibitor potentiation of glioma cells to temozolomide Tang, Jiang-bo; Svilar, David; Trivedi, Ram N. Neuro-Oncology, Vol. 13, Issue 5 https://doi.org/10.1093/neuonc/nor011	journal	March 2011
PARP and PARG inhibitors in cancer treatment Slade, Dea Genes & Development, Vol. 34, Issue 5-6 https://doi.org/10.1101/gad.334516.119	journal	February 2020
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Blu-Ice and the Distributed Control System : software for data acquisition and instrument control at macromolecular crystallography beamlines McPhillips, Timothy M.; McPhillips, Scott E.; Chiu, Hsiu-Ju Journal of Synchrotron Radiation, Vol. 9, Issue 6 https://doi.org/10.1107/S0909049502015170	journal	November 2002
Frequent Co‐Alterations of TP53, p16/CDKN2A, p14^ARF, PTEN Tumor Suppressor Genes in Human Glioma Cell Lines. Ishii, Nobuaki; Maier, Daniel; Merlo, Adrian Brain Pathology, Vol. 9, Issue 3 https://doi.org/10.1111/j.1750-3639.1999.tb00536.x	journal	July 1999
Potent Inhibition of Human Apurinic/Apyrimidinic Endonuclease 1 by Arylstibonic Acids Seiple, Lauren A.; Cardellina, John H.; Akee, Rhone Molecular Pharmacology, Vol. 73, Issue 3 https://doi.org/10.1124/mol.107.042622	journal	November 2007
Bypass of DNA Lesions Generated During Anticancer Treatment with Cisplatin by DNA Polymerase Alt, A.; Lammens, K.; Chiocchini, C. Science, Vol. 318, Issue 5852 https://doi.org/10.1126/science.1148242	journal	November 2007
Discovering High-Affinity Ligands for Proteins: SAR by NMR Shuker, S. B.; Hajduk, P. J.; Meadows, R. P. Science, Vol. 274, Issue 5292, p. 1531-1534 https://doi.org/10.1126/science.274.5292.1531	journal	November 1996
Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress Yao, Rui; Shi, Liujia; Wu, Chengjin Applied and Environmental Microbiology, Vol. 85, Issue 1 https://doi.org/10.1128/AEM.01988-18	journal	January 2019
Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism Yang, Wei; Gao, Yang Annual Review of Biochemistry, Vol. 87, Issue 1 https://doi.org/10.1146/annurev-biochem-062917-012405	journal	June 2018
A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade Ngoi, Natalie Y. L.; Peng, Guang; Yap, Timothy A. Annual Review of Medicine, Vol. 73, Issue 1 https://doi.org/10.1146/annurev-med-042320-025136	journal	January 2022
The Role of DNA Polymerase η in Translesion Synthesis Past Platinum–DNA Adducts in Human Fibroblasts Bassett, Ekaterina; King, Nicole M.; Bryant, Miriam F. Cancer Research, Vol. 64, Issue 18 https://doi.org/10.1158/0008-5472.CAN-04-1328	journal	September 2004
A Role for Polymerase η in the Cellular Tolerance to Cisplatin-Induced Damage Albertella, Mark R.; Green, Catherine M.; Lehmann, Alan R. Cancer Research, Vol. 65, Issue 21 https://doi.org/10.1158/0008-5472.CAN-05-1095	journal	November 2005
DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress Barnes, Ryan P.; Tsao, Wei-Chung; Moldovan, George-Lucian Cancer Research, Vol. 78, Issue 23 https://doi.org/10.1158/0008-5472.CAN-17-3931	journal	October 2018
A PolH Transcript with a Short 3′UTR Enhances PolH Expression and Mediates Cisplatin Resistance Zhang, Jin; Sun, Wenqiang; Ren, Cong Cancer Research, Vol. 79, Issue 14 https://doi.org/10.1158/0008-5472.CAN-18-3928	journal	July 2019
O6-Methylguanine-DNA Methyltransferase, O6-Benzylguanine, and Resistance to Clinical Alkylators in Pediatric Primary Brain Tumor Cell Lines Bobola, Michael S.; Silber, John R.; Ellenbogen, Richard G. Clinical Cancer Research, Vol. 11, Issue 7 https://doi.org/10.1158/1078-0432.CCR-04-2045	journal	April 2005
Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors Bobola, Michael S.; Finn, Laura S.; Ellenbogen, Richard G. Clinical Cancer Research, Vol. 11, Issue 20 https://doi.org/10.1158/1078-0432.CCR-05-1068	journal	October 2005
A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia Gojo, Ivana; Beumer, Jan H.; Pratz, Keith W. Clinical Cancer Research, Vol. 23, Issue 3 https://doi.org/10.1158/1078-0432.CCR-16-0984	journal	January 2017
Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition Wang, Dong; Luo, Meihua; Kelley, Mark R. Molecular Cancer Therapeutics, Vol. 3, Issue 6 https://doi.org/10.1158/1535-7163.679.3.6	journal	June 2004
Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor Perera, Timothy P. S.; Jovcheva, Eleonora; Mevellec, Laurence Molecular Cancer Therapeutics, Vol. 16, Issue 6 https://doi.org/10.1158/1535-7163.MCT-16-0589	journal	June 2017
DNA polymeraseη protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy Teng, Kai-yuan; Qiu, Miao-zhen; Li, Zhuang-hua Journal of Translational Medicine, Vol. 8, Issue 1 https://doi.org/10.1186/1479-5876-8-126	journal	November 2010
Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1 Simeonov, Anton; Kulkarni, Avanti; Dorjsuren, Dorjbal PLoS ONE, Vol. 4, Issue 6 https://doi.org/10.1371/journal.pone.0005740	journal	June 2009
Diverse Small Molecule Inhibitors of Human Apurinic/Apyrimidinic Endonuclease APE1 Identified from a Screen of a Large Public Collection Dorjsuren, Dorjbal; Kim, Daemyung; Vyjayanti, Vaddadi N. PLoS ONE, Vol. 7, Issue 10 https://doi.org/10.1371/journal.pone.0047974	journal	October 2012
Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy Zhou, Wendi; Chen, Yih-wen; Liu, Xiyong PLoS ONE, Vol. 8, Issue 12 https://doi.org/10.1371/journal.pone.0083978	journal	December 2013
Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage Inomata, Yuriko; Abe, Takuya; Tsuda, Masataka PLOS ONE, Vol. 16, Issue 6 https://doi.org/10.1371/journal.pone.0252587	journal	June 2021
Mild phenotype of knockouts of the major apurinic/apyrimidinic endonuclease APEX1 in a non-cancer human cell line Kim, Daria V.; Kulishova, Liliya M.; Torgasheva, Natalia A. PLOS ONE, Vol. 16, Issue 9 https://doi.org/10.1371/journal.pone.0257473	journal	September 2021
Characterizing inhibitors of human AP endonuclease 1 Pidugu, Lakshmi S.; Servius, Hardler W.; Sevdalis, Spiridon E. PLOS ONE, Vol. 18, Issue 1 https://doi.org/10.1371/journal.pone.0280526	journal	January 2023
Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy Abbotts, Rachel; Jewell, Rosalyn; Nsengimana, Jérémie Oncotarget, Vol. 5, Issue 10 https://doi.org/10.18632/oncotarget.1926	journal	April 2014
Research progress of human AP endonuclease 1: structure, catalytic mechanism and inhibitors Zhang, Zelan; Wu, Zhixiang; Shi, Xiaodong Current Protein & Peptide Science, Vol. 23 https://doi.org/10.2174/1389203723666220406132737	journal	April 2022
Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist Wang, Haiyan; Cai, Shanbao; Bailey, Barbara J. Journal of Neurosurgery, Vol. 126, Issue 2 https://doi.org/10.3171/2016.1.JNS152513	journal	February 2017
Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro Frontiers in Oncology, Vol. 2 https://doi.org/10.3389/fonc.2012.00186	journal	January 2012
Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH) Wilson, David M.; Duncton, Matthew A. J.; Chang, Caleb Frontiers in Oncology, Vol. 11 https://doi.org/10.3389/fonc.2021.778925	journal	November 2021
Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass Wilkinson, Nicole A.; Mnuskin, Katherine S.; Ashton, Nicholas W. Cancers, Vol. 12, Issue 10 https://doi.org/10.3390/cancers12102848	journal	October 2020
Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer Gorecki, Lukas; Andrs, Martin; Korabecny, Jan Cancers, Vol. 13, Issue 4 https://doi.org/10.3390/cancers13040795	journal	February 2021
Nontraditional Roles of DNA Polymerase Eta Support Genome Duplication and Stability Eckert, Kristin A. Genes, Vol. 14, Issue 1 https://doi.org/10.3390/genes14010175	journal	January 2023
Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency Chen, Cho-Yi; Kawasumi, Masaoki; Lan, Tien-Yun International Journal of Molecular Sciences, Vol. 22, Issue 1 https://doi.org/10.3390/ijms22010355	journal	December 2020

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