Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275

Abstract

L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.