Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor

Abstract

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.

Biochemical and Structural Studies of LjSK1, a Lotus japonicus GSK3β/SHAGGY-like Kinase, Reveal Its Functional Role

“…46 Therefore, we investigated whether triterpenoids can modulate the LjSK1 activity. Three triterpenoids were selected, betulinic acid which has been reported to inhibit GSK3β, 17 lupeol which has been reported to have a role in nodule formation 16 like LjSK1, 9 and HedC, a saponin found in H. helix leaves which has been reported to have activity against GSK3β. 47 The inhibitory potency of these three compounds to LjSK1 has been determined, and their IC 50 values are presented in Table 2.…”

“…Based on these findings, it is evident that LjSK1 constitutes a potential target for crop manipulation. Therefore, to initiate structure-based discovery studies for activity modulators, we have studied the binding to LjSK1 of betulinic acid (a well-known phytogenic molecule that inhibits kinases including GSK3), and hederacoside C (HedC), a natural triterpenoidal glycoside mainly isolated from the fruits of Hedera helix . Our results have shown that HedC can be the starting point for the further design of LjSK1 activity modulators.…”