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

Abstract

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.

Authors:
 [1];  [1]; ORCiD logo [2];  [3];  [2]; ORCiD logo [2];  [4];  [5];  [6];  [2];  [7]; ORCiD logo [2];  [8]; ORCiD logo [9];  [10]; ORCiD logo [4];  [8]; ORCiD logo [11]; ORCiD logo [5];  [2] more »; ORCiD logo [2] « less
  1. Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology
  2. Univ. of Texas, Houston, TX (United States). Depts. of Cancer Biology and of Molecular and Cellular Oncology
  3. 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
  4. Harvard Univ., Cambridge, MA (United States). School of Public Health
  5. 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
  6. Univ. of Cincinnati, OH (United States). Dept. of Chemistry
  7. 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
  8. Washington Univ., St. Louis, MO (United States). School of Medicine, Dept. of Biochemistry and Molecular Biophysics
  9. 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
  10. 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
  11. 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
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1624221
Grant/Contract Number:  
AC02-76SF00515; R01 CA200231; P01 CA092584; R35CA22043; P41 GM103393; ACI-1134872
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics

Citation Formats

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, and Tainer, John A.. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. United States: N. p., 2019. Web. https://doi.org/10.1038/s41467-019-13508-4.
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.. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. United States. https://doi.org/10.1038/s41467-019-13508-4
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, and Tainer, John A.. Wed . "Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death". United States. https://doi.org/10.1038/s41467-019-13508-4. https://www.osti.gov/servlets/purl/1624221.
@article{osti_1624221,
title = {Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death},
author = {Houl, Jerry H. and Ye, Zu and Brosey, Chris A. and Balapiti-Modarage, Lakshitha P. F. and Namjoshi, Sarita and Bacolla, Albino and Laverty, Daniel and Walker, Brian L. and Pourfarjam, Yasin and Warden, Leslie S. and Babu Chinnam, Naga and Moiani, Davide and Stegeman, Roderick A. and Chen, Mei-Kuang and Hung, Mien-Chie and Nagel, Zachary D. and Ellenberger, Tom and Kim, In-Kwon and Jones, Darin E. and Ahmed, Zamal and Tainer, John A.},
abstractNote = {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.},
doi = {10.1038/s41467-019-13508-4},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {12}
}

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    Works referencing / citing this record:

    Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases
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    • Wazir, Sarah; Maksimainen, Mirko M.; Alanen, Heli I.
    • SLAS DISCOVERY: Advancing the Science of Drug Discovery
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