Flavonoids as Protein Kinase Inhibitors for Cancer Chemoprevention: Direct Binding and Molecular Modeling

Protein kinases play crucial roles in the regulation of multiple cell signaling pathways and cellular functions. Deregulation of protein kinase function has been implicated in carcinogenesis. The inhibition of protein kinases has emerged as an important target for cancer chemoprevention and therapy. Accumulated data revealed that flavonoids exert chemopreventive effects through acting at protein kinase signaling pathways, more than as conventional hydrogen-donating antioxidants. Recent studies show that flavonoids can bind directly to some protein kinases, including Akt/protein kinase B (Akt/PKB), Fyn, Janus kinase 1 (JAK1), mitogen-activated protein kinase kinase 1 (MEK1), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase kinase 4 (MKK4), Raf1, and ζ chain-associated 70-kDa protein (ZAP-70) kinase, and then alter their phosphorylation state to regulate multiple cell signaling pathways in carcinogenesis processes. In this review, we report recent results on the interactions of flavonoids and protein kinases, especially their direct binding and molecular modeling. The data suggest that flavonoids act as protein kinase inhibitors for cancer chemoprevention that were thought previously as conventional hydrogen-donating antioxidant. Moreover, the molecular modeling data show some hints for creating natural compound-based protein kinase inhibitors for cancer chemoprevention and therapy. Antioxid. Redox Signal. 13, 691–719. Introduction Methodologies for Direct Binding Detection and Molecular Modeling of Flavonoid–Protein Kinase Cyanogen bromide–activated Sepharose 4B beads couple with flavonoids Affinity analysis of flavonoid–protein kinase interaction SPR QCM [3H]-labeled flavonoids Molecular modeling of flavonoid–protein kinase docking Direct Binding and Molecular Modeling of Flavonoids to Protein Kinases Myricetin–JAK1, Akt, MEK1, Fyn, MKK4, and PI3K JAK1 Akt MEK1 Fyn MKK4 PI3K Delphinidin–Raf1, MEK1, Fyn Raf1 and MEK1 Fyn EGCG–ZAP-70, Fyn ZAP-70 Fyn Quercetin–MEK1, PI3K MEK1 PI3K Caffeic acid–Fyn Equol–MEK1 RSVL2–MEK1 Procyanidins–MEK1, MKK4 MEK1 MKK4 Signaling Pathways Regulated by Direct Binding of Flavonoid–Protein Kinase PI3K–Akt signaling Raf–MEK1–MAPK signaling JAK–STAT3 signaling Binding Sites and Protein Kinase Selectivity of Flavonoids The sites of flavonoids binding to protein kinases ATP-binding site Activation loop Allosteric site Affinity of flavonoid binding to protein kinases Multiple targets vs. selectivity Remarks and Perspectives