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

Jerry H. Houl, Zu Ye, Chris A. Brosey, Lakshitha P. F. Balapiti-Modarage, Sarita Namjoshi, Albino Bacolla, Daniel Laverty, Brian L. Walker, Yasin Pourfarjam, Leslie S. Warden, Naga Babu Chinnam, Davide Moiani, Roderick A. Stegeman, Mei-Kuang Chen, Mien-Chie Hung, Zachary D. Nagel, Tom Ellenberger, In-Kwon Kim (), Darin E. Jones, Zamal Ahmed () and John A. Tainer ()
Additional contact information
Jerry H. Houl: University of Texas MD Anderson Cancer Center
Zu Ye: University of Texas MD Anderson Cancer Center
Chris A. Brosey: University of Texas MD Anderson Cancer Center
Lakshitha P. F. Balapiti-Modarage: The University of Arkansas at Little Rock
Sarita Namjoshi: University of Texas MD Anderson Cancer Center
Albino Bacolla: University of Texas MD Anderson Cancer Center
Daniel Laverty: Harvard University, School of Public Health
Brian L. Walker: The University of Arkansas at Little Rock
Yasin Pourfarjam: University of Cincinnati
Leslie S. Warden: University of Texas MD Anderson Cancer Center
Naga Babu Chinnam: University of Texas MD Anderson Cancer Center
Davide Moiani: University of Texas MD Anderson Cancer Center
Roderick A. Stegeman: Washington University School of Medicine
Mei-Kuang Chen: University of Texas MD Anderson Cancer Center
Mien-Chie Hung: University of Texas MD Anderson Cancer Center
Zachary D. Nagel: Harvard University, School of Public Health
Tom Ellenberger: Washington University School of Medicine
In-Kwon Kim: University of Cincinnati
Darin E. Jones: The University of Arkansas at Little Rock
Zamal Ahmed: University of Texas MD Anderson Cancer Center
John A. Tainer: University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-13508-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13508-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-13508-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().