Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: advantages in comparison with competitive inhibitors.

A new series of IGF-1R inhibitors related to hydantoins were identified from a lead originating from HTS. Their noncompetitive property as well as their slow binding characteristics provided a series of compounds with unique selectivity and excellent cellular activities.

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 factor receptor (EGF-R) associated protein tyrosine kinase (PTK) activity as antitumor agents, several families of phenylhydroquinone derivatives were synthesized. Some of these compounds were shown to block PTK activity in vitro, but also efficiently to inhibit EGF-stimulated DNA synthesis in ER 22 cells (CCL 39 hamster fibroblasts transfected with EGF-R) with IC50 values in the range 1-10 microM. In some cases, a correlation between the two sets of data was observed, allowing structure-activity relationships to be established.

Synthesis and biological evaluation of a series of hydroxybenzylphenylamine derivatives as inhibitors of EGF receptor-associated tyrosine kinase activity.

In order to obtain non-degradable and more potent protein-tyrosine kinase inhibitors, derived from the 5-(2,5-dihydroxybenzyl)-aminosalicylates already described, we have developed a new series of 5-(2,5-dihydroxybenzyl)phenylamines. The compounds, diversely substituted on the phenyl ring by alcohol, nitrile, ether, ketone, amide and thioamide groups, were tested for their ability to inhibit epidermal growth factor (EGF) receptor-associated tyrosine kinase activity in vitro. They inhibit the phosphorylation of the peptide substrate RR-Src by the EGF receptor purified from ER 22 cells, with IC50 values in the range 0.

Inhibition of the EGF-stimulated cellular proliferation of ER 22 cells by hydroxybiphenyl derivatives.

Several series of hydroxybiphenyl compounds substituted by a hydrophobic group (tert-butyl or phenyl) and bearing a free or protected carboxylic moiety were synthesized. The compounds were tested for their ability to inhibit the intrinsic tyrosine protein kinase activity of the EGF-receptor in vitro and the EGF-stimulated DNA-synthesis by ER 22 cells. Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 microM), most of them inhibited the EGF-dependent cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.

Cloning of a Grb2 isoform with apoptotic properties.

Growth factor receptor-bound protein 2 (Grb2) links tyrosine-phosphorylated proteins to a guanine nucleotide releasing factor of the son of sevenless (Sos) class by attaching to the former by its Src homology 2 (SH2) moiety and to the latter by its SH3 domains. An isoform of grb2 complementary DNA (cDNA) was cloned that has a deletion in the SH2 domain. The protein encoded by this cDNA, Grb3-3, did not bind to phosphorylated epidermal growth factor receptor (EGFR) but retained functional SH3 domains and inhibited EGF-induced transactivation of a Ras-responsive element.