Screening and discovery of nitro-benzoxadiazole compounds activating epidermal growth factor receptor (EGFR) in cancer cells.
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.
1] ProtNeteomix, 29 rue de Provence, 44700 Orvault, France [2] IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
Vehary
V
Sakanyan
ProtNeteomix, 29 rue de Provence, 44700 Orvault, France.
Marie
M
Angelini
FRE-CNRS 3478, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
Mickael
M
Le Béchec
ProtNeteomix, 29 rue de Provence, 44700 Orvault, France.
Michèle Françoise
MF
Lecocq
IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
Florence
F
Benaiteau
IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
Bénédicte
B
Rousseau
Institute of Biochemistry, National Academy of Sciences of Armenia, Yerevan, Republic of Armenia.
Aram
A
Gyulkhandanyan
Institute of Biochemistry, National Academy of Sciences of Armenia, Yerevan, Republic of Armenia.
Lusine
L
Gyulkhandanyan
IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
Cédric
C
Logé
BIOS group, UMR85 INRA; UMR7247 CNRS; IFCE, 37380 Nouzilly, France.
Eric
E
Reiter
IICIMED-EA 1155, UFR Sciences Pharmaceutiques, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière 44322 Nantes, France.
Christos
C
Roussakis
FRE-CNRS 3478, UFR Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière, 44322 Nantes, France.
Fabrice
F
Fleury
D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D009574:Nitro Compounds / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D010069:Oxadiazoles; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline