2. Academic Validation
  3. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

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

  • Nat Commun. 2019 Dec 11;10(1):5654. doi: 10.1038/s41467-019-13508-4.
Jerry H Houl 1,  Zu Ye 1,  Chris A Brosey 1,  Lakshitha P F Balapiti-Modarage 2 3,  Sarita Namjoshi 1,  Albino Bacolla 1,  Daniel Laverty 4,  Brian L Walker 2 3,  Yasin Pourfarjam 5,  Leslie S Warden 1,  Naga Babu Chinnam 1 6,  Davide Moiani 1,  Roderick A Stegeman 7,  Mei-Kuang Chen 1 6,  Mien-Chie Hung 1 8,  Zachary D Nagel 4,  Tom Ellenberger 7,  In-Kwon Kim 9 10,  Darin E Jones 2 3,  Zamal Ahmed 11,  John A Tainer 12
Affiliations

Affiliations

  • 1 Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • 2 Department of Chemistry, The University of Arkansas at Little Rock, 2801S. University Ave, Little Rock, AR, 72204, USA.
  • 3 Department of Pharmaceutical Sciences, The University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA.
  • 4 Harvard University, School of Public Health, Boston, MA, 02115, USA.
  • 5 Department of Chemistry, University of Cincinnati, 301 Clifton Ct, Cincinnati, OH, 45221, USA.
  • 6 The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 7 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660S. Euclid Avenue, Saint Louis, MO, 63110, USA.
  • 8 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President, China Medical University, Taichung, 404, Taiwan.
  • 9 Department of Chemistry, University of Cincinnati, 301 Clifton Ct, Cincinnati, OH, 45221, USA. [email protected].
  • 10 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660S. Euclid Avenue, Saint Louis, MO, 63110, USA. [email protected].
  • 11 Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA. [email protected].
  • 12 Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA. [email protected].
PMID: 31827085 DOI: 10.1038/s41467-019-13508-4
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.

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