Screening and Discovery of Nitro-benzoxadiazole Compounds Activating Epidermal Growth Factor Receptor (EGFR) in Cancer Cells

Overview

Journal Sci Rep

Specialty Science

Date 2014 Feb 6

PMID 24496106

Citations 7

Authors

Vehary Sakanyan

Marie Angelini

Mickael Le Bechec

Michele Francoise Lecocq

Florence Benaiteau

Benedicte Rousseau

Aram Gyulkhandanyan

Lusine Gyulkhandanyan

Cedric Loge

Eric Reiter

Christos Roussakis

Fabrice Fleury

Affiliations

Soon will be listed here.

Abstract

Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other receptor tyrosine kinases in cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in cancer cells exposed to electrophilic NBD compounds.

Citing Articles

Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer.

Sakanyan V, Iradyan N, Alves de Sousa R BioTech (Basel). 2023; 12(3).

PMID: 37754201 PMC: 10526213. DOI: 10.3390/biotech12030057.

In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice.

Bhat Z, Kumar M, Sharma N, Yadav U, Singh T, Joshi G Molecules. 2022; 27(17).

PMID: 36080307 PMC: 9457798. DOI: 10.3390/molecules27175540.

Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase.

Berggren G, Sahlin M, Crona M, Tholander F, Sjoberg B J Biol Inorg Chem. 2019; 24(6):841-848.

PMID: 31218442 PMC: 6754346. DOI: 10.1007/s00775-019-01679-w.

Deficiency in the secreted protein Semaphorin3d causes abnormal parathyroid development in mice.

Singh A, Mia M, Cibi D, Arya A, Bhadada S, Singh M J Biol Chem. 2019; 294(21):8336-8347.

PMID: 30979723 PMC: 6544867. DOI: 10.1074/jbc.RA118.007063.

Reactive Chemicals and Electrophilic Stress in Cancer: A Minireview.

Sakanyan V High Throughput. 2018; 7(2).

PMID: 29702613 PMC: 6023294. DOI: 10.3390/ht7020012.

References

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

Weidner K, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996; 384(6605):173-6. DOI: 10.1038/384173a0. View

Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim J . Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002; 110(6):775-87. DOI: 10.1016/s0092-8674(02)00963-7. View

Liu F, Chernoff J . Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochem J. 1997; 327 ( Pt 1):139-45. PMC: 1218773. DOI: 10.1042/bj3270139. View

Wilson K, Gilmore J, Foley J, Lemmon M, Riese 2nd D . Functional selectivity of EGF family peptide growth factors: implications for cancer. Pharmacol Ther. 2009; 122(1):1-8. PMC: 2665203. DOI: 10.1016/j.pharmthera.2008.11.008. View

Goldkorn T, Balaban N, Matsukuma K, Chea V, Gould R, Last J . EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am J Respir Cell Mol Biol. 1998; 19(5):786-98. DOI: 10.1165/ajrcmb.19.5.3249. View

Lohse D, Denu J, Santoro N, Dixon J . Roles of aspartic acid-181 and serine-222 in intermediate formation and hydrolysis of the mammalian protein-tyrosine-phosphatase PTP1. Biochemistry. 1997; 36(15):4568-75. DOI: 10.1021/bi963094r. View

DeYulia Jr G, Carcamo J . EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases. Biochem Biophys Res Commun. 2005; 334(1):38-42. DOI: 10.1016/j.bbrc.2005.06.056. View

Earp H, Dawson T, Li X, Yu H . Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat. 1995; 35(1):115-32. DOI: 10.1007/BF00694752. View

10.

Ferrari E, Tinti M, Costa S, Corallino S, Nardozza A, Chatraryamontri A . Identification of new substrates of the protein-tyrosine phosphatase PTP1B by Bayesian integration of proteome evidence. J Biol Chem. 2010; 286(6):4173-85. PMC: 3039405. DOI: 10.1074/jbc.M110.157420. View

11.

Foong Y, Fu J, Yao S, Uttamchandani M . Current advances in peptide and small molecule microarray technologies. Curr Opin Chem Biol. 2012; 16(1-2):234-42. DOI: 10.1016/j.cbpa.2011.12.007. View

12.

Wang Y, Hung M . Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family. Cell Biosci. 2012; 2(1):13. PMC: 3418567. DOI: 10.1186/2045-3701-2-13. View

13.

Carlson S, White F . Using small molecules and chemical genetics to interrogate signaling networks. ACS Chem Biol. 2010; 6(1):75-85. DOI: 10.1021/cb1002834. View

14.

Peternel S, Grdadolnik J, Gaberc-Porekar V, Komel R . Engineering inclusion bodies for non denaturing extraction of functional proteins. Microb Cell Fact. 2008; 7:34. PMC: 2630956. DOI: 10.1186/1475-2859-7-34. View

15.

Kamata H, Shibukawa Y, Oka S, Hirata H . Epidermal growth factor receptor is modulated by redox through multiple mechanisms. Effects of reductants and H2O2. Eur J Biochem. 2000; 267(7):1933-44. DOI: 10.1046/j.1432-1327.2000.01194.x. View

16.

Lavis L, Raines R . Bright ideas for chemical biology. ACS Chem Biol. 2008; 3(3):142-55. PMC: 2802578. DOI: 10.1021/cb700248m. View

17.

Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio P . Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 2011; 71(8):3132-41. DOI: 10.1158/0008-5472.CAN-10-2662. View

18.

Dawson J, Berger M, Lin C, Schlessinger J, Lemmon M, Ferguson K . Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol. 2005; 25(17):7734-42. PMC: 1190273. DOI: 10.1128/MCB.25.17.7734-7742.2005. View

19.

Kemp M, Weiwer M, Koehler A . Unbiased binding assays for discovering small-molecule probes and drugs. Bioorg Med Chem. 2012; 20(6):1979-89. DOI: 10.1016/j.bmc.2011.11.071. View

20.

Patridge E, Eriksson E, Penketh P, Baumann R, Zhu R, Shyam K . 7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide. Arch Toxicol. 2012; 86(10):1613-25. PMC: 3781597. DOI: 10.1007/s00204-012-0872-9. View