title: Tyrphostin AG 494 blocks Cdk2 activation.
abstract: We have previously shown that the EGFR kinase selective tyrphostin AG 494 fails to inhibit EGFR kinase in intact cells. Yet, AG 494 proved to inhibit EGF- or serum-induced cell proliferation (Osherov et al., J. Biol. Chem. 268 (1993) 11134-11142). In this preliminary communication we show that AG 494 as well as its close analogs AG 490 and AG 555 block Cdk2 activation. In contrast, AG 1478, a more selective EGFR kinase blocker which is also active as EGFR kinase blocker in intact cells, fails to do so. AG 494 exerts its full inhibitory activity on Cdk2 activation even when added 20 h subsequent to EGF addition when Cdk2 activation is maximal. The inhibitory activity on Cdk2 activation parallels its DNA synthesis inhibitory activity, strongly suggesting that its target is one of the molecular mechanisms involved in Cdk2 activation. AG 494 and its analogs may become useful lead compounds for the development of drugs aimed at the cell cycle machinery.
authors.affiliation: Department of Biological Chemistry, Alexander Silverman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Osherov
authors.forename: A
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D016475:3T3 Cells; D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D020032:Tyrphostins
chemical_list: D000178:Acrylamides; D004791:Enzyme Inhibitors; D009570:Nitriles; D011799:Quinazolines; D020032:Tyrphostins; C107502:AG 494; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases