Accéder au contenu
Merck

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

Nature communications (2019-12-13)
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, John A Tainer
RÉSUMÉ

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.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Crystal violet, ACS reagent, ≥90.0% anhydrous basis
Sigma-Aldrich
5-Chloro-2′-deoxyuridine, thymidine analog
Sigma-Aldrich
JA2131, ≥98% (HPLC)