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 · 11 December 2019 · Nature Communications

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

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

^[2]; Balapiti-Modarage, Lakshitha P. F. ^[3]; Namjoshi, Sarita ^[2];

^[2]; Laverty, Daniel ^[4]; Walker, Brian L. ^[5]; Pourfarjam, Yasin ^[6]; Warden, Leslie S. ^[2]; Babu Chinnam, Naga ^[7];

^[2]; Stegeman, Roderick A. ^[8];

^[9]; Hung, Mien-Chie ^[10];

^[4]; Ellenberger, Tom ^[8];

^[11];

^[5]; Ahmed, Zamal ^[2] more »

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; Univ. of Texas, Houston, TX (United States). UTHealth Graduate School of Biomedical Sciences
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 Laboratory (SLAC), Menlo Park, CA (United States)

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

Grant/Contract Number:: AC02-76SF00515; R01 CA200231; P01 CA092584; R35CA22043; P41 GM103393; ACI-1134872

OSTI ID:: 1624221

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

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 59 works

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Drilling accurate nanopores for biosensors by energetic multi-wall carbon nanotubes: a molecular dynamics investigation Li, Changsheng; Wang, Zilin; Ma, Lei Journal of Molecular Modeling, Vol. 28, Issue 10 https://doi.org/10.1007/s00894-022-05276-8	journal	September 2022
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
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
SAR Analysis of Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol Inhibition of Poly(ADP-ribose) Glycohydrolase Koh, David W.; Coyle, Donna L.; Mehta, Nimish Journal of Medicinal Chemistry, Vol. 46, Issue 20 https://doi.org/10.1021/jm020541u	journal	September 2003
The expanding role of poly(ADP-ribose) metabolism: current challenges and new perspectives Gagné, Jean-Philippe; Hendzel, Michael J.; Droit, Arnaud Current Opinion in Cell Biology, Vol. 18, Issue 2 https://doi.org/10.1016/j.ceb.2006.02.013	journal	April 2006
Poly(ADP-ribose) glycohydrolase as a target for neuroprotective intervention: assessment of currently available pharmacological tools Falsig, Jeppe; Christiansen, Søren Hofman; Feuerhahn, Sascha European Journal of Pharmacology, Vol. 497, Issue 1 https://doi.org/10.1016/j.ejphar.2004.06.042	journal	August 2004
Structure of mammalian poly(ADP-ribose) glycohydrolase reveals a flexible tyrosine clasp as a substrate-binding element Kim, In-Kwon; Kiefer, James R.; Ho, Chris M. W. Nature Structural & Molecular Biology, Vol. 19, Issue 6 https://doi.org/10.1038/nsmb.2305	journal	May 2012
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
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
Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe Margalef, Pol; Kotsantis, Panagiotis; Borel, Valerie Cell, Vol. 172, Issue 3 https://doi.org/10.1016/j.cell.2017.11.047	journal	January 2018
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
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
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
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality Gogola, Ewa; Duarte, Alexandra A.; de Ruiter, Julian R. Cancer Cell, Vol. 35, Issue 6 https://doi.org/10.1016/j.ccell.2019.05.012	journal	June 2019
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase Garcin, Elsa D.; Arvai, Andrew S.; Rosenfeld, Robin J. Nature Chemical Biology, Vol. 4, Issue 11 https://doi.org/10.1038/nchembio.115	journal	October 2008
The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase Slade, Dea; Dunstan, Mark S.; Barkauskaite, Eva Nature, Vol. 477, Issue 7366 https://doi.org/10.1038/nature10404	journal	September 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
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
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
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
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
Selective Small Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG) Finch, Kristin E.; Knezevic, Claire E.; Nottbohm, Amanda C. ACS Chemical Biology, Vol. 7, Issue 3 https://doi.org/10.1021/cb200506t	journal	January 2012
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
Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease Sharifi, Reza; Morra, Rosa; Denise Appel, C. The EMBO Journal, Vol. 32, Issue 9 https://doi.org/10.1038/emboj.2013.51	journal	March 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
Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities Barkauskaite, Eva; Brassington, Amy; Tan, Edwin S. Nature Communications, Vol. 4, Issue 1 https://doi.org/10.1038/ncomms3164	journal	August 2013
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 dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways Shirai, H.; Poetsch, A. R.; Gunji, A. Cell Death & Disease, Vol. 4, Issue 6 https://doi.org/10.1038/cddis.2013.133	journal	June 2013
Specific Inhibition of Poly(ADP-ribose) Glycohydrolase by Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol Slama, James T.; Aboul-Ela, Nasreen; Goli, Deepa M. Journal of Medicinal Chemistry, Vol. 38, Issue 2 https://doi.org/10.1021/jm00002a021	journal	January 1995
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
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
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
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

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Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases Wazir, Sarah; Maksimainen, Mirko M.; Alanen, Heli I. SLAS DISCOVERY: Advancing the Science of Drug Discovery https://doi.org/10.1177/2472555220928911	journal	June 2020

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