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 μM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC₅₀ = 0.4 μM). This inhibition was competitive with respect to ATP (K_iATP= 0.041 μM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH₂, K_iCDK1S1 = 0.14 μM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.