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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.
Afiliação
  • Houl JH; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Ye Z; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Brosey CA; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Balapiti-Modarage LPF; Department of Chemistry, The University of Arkansas at Little Rock, 2801S. University Ave, Little Rock, AR, 72204, USA.
  • Namjoshi S; Department of Pharmaceutical Sciences, The University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA.
  • Bacolla A; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Laverty D; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Walker BL; Harvard University, School of Public Health, Boston, MA, 02115, USA.
  • Pourfarjam Y; Department of Chemistry, The University of Arkansas at Little Rock, 2801S. University Ave, Little Rock, AR, 72204, USA.
  • Warden LS; Department of Pharmaceutical Sciences, The University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA.
  • Babu Chinnam N; Department of Chemistry, University of Cincinnati, 301 Clifton Ct, Cincinnati, OH, 45221, USA.
  • Moiani D; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Stegeman RA; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Chen MK; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • Hung MC; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Nagel ZD; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660S. Euclid Avenue, Saint Louis, MO, 63110, USA.
  • Ellenberger T; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Kim IK; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • Jones DE; Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA.
  • Ahmed Z; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President, China Medical University, Taichung, 404, Taiwan.
  • Tainer JA; Harvard University, School of Public Health, Boston, MA, 02115, USA.
Nat Commun ; 10(1): 5654, 2019 12 11.
Article em En | MEDLINE | ID: mdl-31827085
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Replicação do DNA / Inibidores Enzimáticos / Bibliotecas de Moléculas Pequenas / Glicosídeo Hidrolases / Neoplasias Tipo de estudo: Etiology_studies Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Replicação do DNA / Inibidores Enzimáticos / Bibliotecas de Moléculas Pequenas / Glicosídeo Hidrolases / Neoplasias Tipo de estudo: Etiology_studies Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos