A New Nitrobenzoxadiazole-based GSTP1-1 Inhibitor with a Previously Unheard of Mechanism of Action and High Stability

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2017 Jan 19

PMID 28097896

Citations 11

Authors

Chiara Fulci

Dante Rotili

Anastasia De Luca

Lorenzo Stella

Blasco Morozzo Della Rocca

Mariantonietta Forgione

Veronica Di Paolo

Antonello Mai

Mattia Falconi

Luigi Quintieri

Anna M Caccuri

Affiliations

Soon will be listed here.

Abstract

Context: The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models.

Objective: To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753.

Materials And Methods: Synthesis of MC2752 and MC2753, biochemical assays and in silico docking and normal-mode analyses.

Results: The presence of a hydrophobic moiety in the side chain of MC2753 confers unique features to this molecule. Unlike its parent drug NBDHEX, MC2753 does not require GSH to trigger the dissociation of the complex between GSTP1-1 and TRAF2, and displays high stability towards the nucleophilic attack of the tripeptide under physiological conditions.

Discussion And Conclusion: MC2753 may represent a lead compound for the development of novel GSTP1-1 inhibitors not affected in their anticancer action by fluctuations of cellular GSH levels, and characterized by an increased half-life in vivo.

Citing Articles

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Inhibition Analysis and High-Resolution Crystal Structure of Glutathione Transferase P1-1.

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Russell T, Richardson D Biomolecules. 2022; 12(9).

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References

Pellizzari Tregno F, Sau A, Pezzola S, Geroni C, Lapenta C, Spada M . In vitro and in vivo efficacy of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on human melanoma. Eur J Cancer. 2009; 45(14):2606-17. DOI: 10.1016/j.ejca.2009.06.033. View

Tentori L, Dorio A, Mazzon E, Muzi A, Sau A, Cuzzocrea S . The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma. Eur J Cancer. 2011; 47(8):1219-30. DOI: 10.1016/j.ejca.2010.12.008. View

De Luca A, Rotili D, Carpanese D, Lenoci A, Calderan L, Scimeca M . A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts. Oncotarget. 2015; 6(6):4126-43. PMC: 4414177. DOI: 10.18632/oncotarget.2798. View

Wu Y, Fan Y, Xue B, Luo L, Shen J, Zhang S . Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. Oncogene. 2006; 25(42):5787-800. DOI: 10.1038/sj.onc.1209576. View

Sau A, Filomeni G, Pezzola S, DAguanno S, Pellizzari Tregno F, Urbani A . Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. Mol Biosyst. 2011; 8(4):994-1006. DOI: 10.1039/c1mb05295k. View

Hegazy U, Mannervik B, Stenberg G . Functional role of the lock and key motif at the subunit interface of glutathione transferase p1-1. J Biol Chem. 2003; 279(10):9586-96. DOI: 10.1074/jbc.M312320200. View

Rotili D, De Luca A, Tarantino D, Pezzola S, Forgione M, Morozzo Della Rocca B . Synthesis and structure--activity relationship of new cytotoxic agents targeting human glutathione-S-transferases. Eur J Med Chem. 2014; 89:156-71. DOI: 10.1016/j.ejmech.2014.10.033. View

Sau A, Pellizzari Tregno F, Valentino F, Federici G, Caccuri A . Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys. 2010; 500(2):116-22. DOI: 10.1016/j.abb.2010.05.012. View

De Luca A, Federici L, De Canio M, Stella L, Caccuri A . New insights into the mechanism of JNK1 inhibition by glutathione transferase P1-1. Biochemistry. 2012; 51(37):7304-12. DOI: 10.1021/bi300559m. View

10.

Ricci G, De Maria F, Antonini G, Turella P, Bullo A, Stella L . 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem. 2005; 280(28):26397-405. DOI: 10.1074/jbc.M503295200. View

11.

Turella P, Cerella C, Filomeni G, Bullo A, De Maria F, Ghibelli L . Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res. 2005; 65(9):3751-61. DOI: 10.1158/0008-5472.CAN-04-3903. View

12.

De Luca A, Mei G, Rosato N, Nicolai E, Federici L, Palumbo C . The fine-tuning of TRAF2-GSTP1-1 interaction: effect of ligand binding and in situ detection of the complex. Cell Death Dis. 2014; 5:e1015. PMC: 4040697. DOI: 10.1038/cddis.2013.529. View

13.

Ricci G, Caccuri A, Lo Bello M, Parker M, Nuccetelli M, Turella P . Glutathione transferase P1-1: self-preservation of an anti-cancer enzyme. Biochem J. 2003; 376(Pt 1):71-6. PMC: 1223740. DOI: 10.1042/BJ20030860. View