SYNTHESIS AND BIOLOGICAL EVALUATION OF A NEW SERIES OF PHENYLHYDROQUINONE DERIVATIVES AS INHIBITORS OF EGF-R-ASSOCIATED PTK ACTIVITY

In order to design new potent inhibitors of the epidermal growth facto r receptor (EGF-R) associated protein tyrosine kinase (PTK) activity a s antitumor agents, several families of phenylhydroquinone derivatives were synthesized. Some of these compounds were shown to block PTK act ivity in vitro, but also efficiently to inhibit EGF-stimulated DNA syn thesis in ER 22 cells (CCL 39 hamster fibroblasts transfected with EGF -R) with IC50 values in the range 1-10 mu M. In some cases. a correlat ion between the two sets of data was observed, allowing structure-acti vity relationships to be established. However, inhibitors which had in vitro specificity with regard to other kinases were not specific in t he cellular test. Similar effects on DNA synthesis were observed after stimulation by various activating agents, suggesting that our compoun ds may also act against other cellular targets involved in the EGF-dep endent pathways leading to cell proliferation.