Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Houl, Jerry H.; Ye, Zu; Brosey, Chris A.; Balapiti-Modarage, Lakshitha P.  F.; Namjoshi, Sarita; Bacolla, Albino; Laverty, Daniel; Walker, Brian L.; Pourfarjam, Yasin; Warden, Leslie S.; Babu Chinnam, Naga; Moiani, Davide; Stegeman, Roderick A.; Chen, Mei-Kuang; Hung, Mien-Chie; Nagel, Zachary D.; Ellenberger, Tom; Kim, In-Kwon; Jones, Darin E.; Ahmed, Zamal; Tainer, John A.

doi:10.1038/s41467-019-13508-4

Title: Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Journal Article · 10 December 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-13508-4 · OSTI ID:1624221

Houl, Jerry H. ^[1]; Ye, Zu ^[2];

^[3]; Balapiti-Modarage, Lakshitha P. F. ^[4]; Namjoshi, Sarita ^[3];

^[3]; Laverty, Daniel ^[5]; Walker, Brian L. ^[6]; Pourfarjam, Yasin ^[7]; Warden, Leslie S. ^[3]; Babu Chinnam, Naga ^[8];

^[3]; Stegeman, Roderick A. ^[9];

^[8]; Hung, Mien-Chie ^[10];

^[5]; Ellenberger, Tom ^[9];

^[11];

^[6]; Ahmed, Zamal ^[3] more »

Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology; DOE/OSTI
Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology
Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology
Univ. of Arkansas, Little Rock, AR (United States). Dept. of Chemistry; Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences
Harvard Univ., Cambridge, MA (United States). School of Public Health
Univ. of Arkansas, Little Rock, AR (United States). Dept. of Chemistry; Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences
Univ. of Cincinnati, OH (United States). Dept. of Chemistry
Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology; Univ. of Texas, Houston, TX (United States). UTHealth Graduate School of Biomedical Sciences
Washington Univ., St. Louis, MO (United States). School of Medicine, Dept. of Biochemistry and Molecular Biophysics
Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology; China Medical University, (Taiwan). Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President
Univ. of Cincinnati, OH (United States). Dept. of Chemistry; Washington Univ., St. Louis, MO (United States). School of Medicine, Dept. of Biochemistry and Molecular Biophysics

Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.

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Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1624221

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality Koh, D. W.; Lawler, A. M.; Poitras, M. F. Proceedings of the National Academy of Sciences, Vol. 101, Issue 51 https://doi.org/10.1073/pnas.0406182101	journal	December 2004
Poly(ADP-ribose) (PAR) polymer is a death signal Andrabi, S. A.; Kim, N. S.; Yu, S. -W. Proceedings of the National Academy of Sciences, Vol. 103, Issue 48 https://doi.org/10.1073/pnas.0606526103	journal	November 2006
Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death Yu, S. -W.; Andrabi, S. A.; Wang, H. Proceedings of the National Academy of Sciences, Vol. 103, Issue 48 https://doi.org/10.1073/pnas.0606528103	journal	November 2006
The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation Mueller-Dieckmann, C.; Kernstock, S.; Lisurek, M. Proceedings of the National Academy of Sciences, Vol. 103, Issue 41 https://doi.org/10.1073/pnas.0606762103	journal	October 2006
A Quantitative Assay Reveals Ligand Specificity of the DNA Scaffold Repair Protein XRCC1 and Efficient Disassembly of Complexes of XRCC1 and the Poly(ADP-ribose) Polymerase 1 by Poly(ADP-ribose) Glycohydrolase Kim, In-Kwon; Stegeman, Roderick A.; Brosey, Chris A. Journal of Biological Chemistry, Vol. 290, Issue 6 https://doi.org/10.1074/jbc.M114.624718	journal	December 2014
TCGA-assembler 2: software pipeline for retrieval and processing of TCGA/CPTAC data Wei, Lin; Jin, Zhilin; Yang, Shengjie Bioinformatics, Vol. 34, Issue 9 https://doi.org/10.1093/bioinformatics/btx812	journal	December 2017
Increased susceptibility of poly(ADP-ribose) polymerase-1 knockout mice to nitrosamine carcinogenicity Tsutsumi, M. Carcinogenesis, Vol. 22, Issue 1 https://doi.org/10.1093/carcin/22.1.1	journal	January 2001
PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanisms Mortusewicz, Oliver; Fouquerel, Elise; Amé, Jean-Christophe Nucleic Acids Research, Vol. 39, Issue 12 https://doi.org/10.1093/nar/gkr099	journal	March 2011
PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion Cuzzocrea, Salvatore; Di Paola, Rosanna; Mazzon, Emanuela The FASEB Journal, Vol. 19, Issue 6 https://doi.org/10.1096/fj.04-3117com	journal	January 2005
Tannic acid, an inhibitor of poly(ADP-ribose) glycohydrolase, sensitizes ovarian carcinoma cells to cisplatin Sun, Yanyan; Zhang, Tianhua; Wang, Beidi Anti-Cancer Drugs, Vol. 23, Issue 9 https://doi.org/10.1097/CAD.0b013e328356359f	journal	January 2012
PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Gupte, Rebecca; Liu, Ziying; Kraus, W. Lee Genes & Development, Vol. 31, Issue 2 https://doi.org/10.1101/gad.291518.116	journal	January 2017
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Integration, scaling, space-group assignment and post-refinement Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 133-144 https://doi.org/10.1107/S0907444909047374	journal	January 2010
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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
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
The finer things in X-ray diffraction data collection Pflugrath, J. W. Acta Crystallographica Section D Biological Crystallography, Vol. 55, Issue 10 https://doi.org/10.1107/S090744499900935X	journal	October 1999
The Stanford Automated Mounter: pushing the limits of sample exchange at the SSRL macromolecular crystallography beamlines Russi, Silvia; Song, Jinhu; McPhillips, Scott E. Journal of Applied Crystallography, Vol. 49, Issue 2 https://doi.org/10.1107/S1600576716000649	journal	February 2016
Targeting dePARylation selectively suppresses DNA repair–defective and PARP inhibitor–resistant malignancies Chen, Shih-Hsun; Yu, Xiaochun Science Advances, Vol. 5, Issue 4 https://doi.org/10.1126/sciadv.aav4340	journal	April 2019
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay Molina, Daniel Martinez; Jafari, Rozbeh; Ignatushchenko, Marina Science, Vol. 341, Issue 6141 https://doi.org/10.1126/science.1233606	journal	July 2013
Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase Ray Chaudhuri, Arnab; Ahuja, Akshay Kumar; Herrador, Raquel Molecular and Cellular Biology, Vol. 35, Issue 5 https://doi.org/10.1128/MCB.01077-14	journal	December 2014
Poly(ADP-Ribose) Polymerase 1 Accelerates Single-Strand Break Repair in Concert with Poly(ADP-Ribose) Glycohydrolase Fisher, Anna E. O.; Hochegger, Helfrid; Takeda, Shunichi Molecular and Cellular Biology, Vol. 27, Issue 15 https://doi.org/10.1128/MCB.02248-06	journal	June 2007
Involvement of Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribosyl)ation in Regulation of Centrosome Function Kanai, Masayuki; Tong, Wei-Min; Sugihara, Eiji Molecular and Cellular Biology, Vol. 23, Issue 7 https://doi.org/10.1128/MCB.23.7.2451-2462.2003	journal	April 2003
Depletion of the 110-Kilodalton Isoform of Poly(ADP-Ribose) Glycohydrolase Increases Sensitivity to Genotoxic and Endotoxic Stress in Mice Cortes, Ulrich; Tong, Wei-Min; Coyle, Donna L. Molecular and Cellular Biology, Vol. 24, Issue 16 https://doi.org/10.1128/MCB.24.16.7163-7178.2004	journal	August 2004
PARG deficiency is neither synthetic lethal with BRCA1 nor PTEN deficiency Noll, Aurélia; Illuzzi, Giuditta; Amé, Jean-Christophe Cancer Cell International, Vol. 16, Issue 1 https://doi.org/10.1186/s12935-016-0333-2	journal	July 2016
Dual activity of PD-L1 targeted Doxorubicin immunoliposomes promoted an enhanced efficacy of the antitumor immune response in melanoma murine model Merino, María; Lozano, Teresa; Casares, Noelia Journal of Nanobiotechnology, Vol. 19, Issue 1 https://doi.org/10.1186/s12951-021-00846-z	journal	April 2021
Radiation-induced mitotic catastrophe in PARG-deficient cells Ame, J. -C.; Fouquerel, E.; Gauthier, L. R. Journal of Cell Science, Vol. 122, Issue 12 https://doi.org/10.1242/jcs.039115	journal	May 2009
Structures of the Human Poly (ADP-Ribose) Glycohydrolase Catalytic Domain Confirm Catalytic Mechanism and Explain Inhibition by ADP-HPD Derivatives Tucker, Julie A.; Bennett, Neil; Brassington, Claire PLoS ONE, Vol. 7, Issue 12 https://doi.org/10.1371/journal.pone.0050889	journal	December 2012
Crystallographic and Biochemical Analysis of the Mouse Poly(ADP-Ribose) Glycohydrolase Wang, Zhizhi; Gagné, Jean-Philippe; Poirier, Guy G. PLoS ONE, Vol. 9, Issue 1 https://doi.org/10.1371/journal.pone.0086010	journal	January 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Overview of the CCP4 suite and current developments. Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.52322	text	January 2011
Poly(ADP-ribose) Glycohydrolase Deficiency Sensitizes Mouse ES Cells to DNA Damaging Agents Fujihara, H.; Ogino, H.; Maeda, D. Current Cancer Drug Targets, Vol. 9, Issue 8 https://doi.org/10.2174/156800909790192419	journal	December 2009
Poly (ADP-ribose) glycohydrolase (PARG) and its therapeutic potential Min, WooKee Frontiers in Bioscience, Vol. Volume, Issue 14 https://doi.org/10.2741/3329	journal	January 2009
The Ups and Downs of Tannins as Inhibitors of Poly(ADP-Ribose)glycohydrolase Blenn, Christian; Wyrsch, Philippe; Althaus, Felix Molecules, Vol. 16, Issue 2 https://doi.org/10.3390/molecules16021854	journal	February 2011
PARG regulates the proliferation and differentiation of DCs and T�cells via PARP/NF‑κB in tumour metastases of colon carcinoma Wang, Jie‑Qiong; Tang, Yi; Li, Qing‑Shu Oncology Reports https://doi.org/10.3892/or.2019.7051	journal	March 2019
Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells Fathers, Catherine; Drayton, Ross M.; Solovieva, Svetlana Cell Cycle, Vol. 11, Issue 5 https://doi.org/10.4161/cc.11.5.19482	journal	March 2012
Poly(ADP-ribosyl)gycohydrolase (PARG) prevents the accumulation of unusual replication structures during unperturbed S phase Ray Chaudhuri, Arnab; Ahuja, Akshay Kumar; Herrador, Raquel American Society for Microbiology https://doi.org/10.5167/uzh-104942	text	January 2014
Correction: Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality Gogola, Ewa; Duarte, Alexandra A.; De Ruiter, Julian R. Cell Press (Elsevier) https://doi.org/10.5167/uzh-172157	text	January 2019
The ups and downs of tannins as inhibitors of poly(ADP-ribose)glycohydrolase Blenn, C.; Wyrsch, P.; Althaus, F. R. MDPI Publishing https://doi.org/10.5167/uzh-58148	text	January 2011
Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases Florian, Rosenthal,; H., Feijs, Karla L.; Emilie, Frugier, Nature Publishing Group https://doi.org/10.5167/uzh-77050	text	January 2013
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Gogola, Ewa; Duarte, Alexandra A.; De Ruiter, Julian R. Cell Press https://doi.org/10.7892/boris.122087	text	January 2018

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