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

Augustine A. Ahmadu (1, 2) , Claire Delehouze (3, 4, 5) , Anas Haruna (2) , Lukman Mustapha (2) , Bilqis A. Lawal (6) , Aniefiok Udobre (7) , Blandine Baratte (3, 4, 8, 9) , Camilla Triscornia (3, 4) , Axelle Autret (5) , Thomas Robert (3, 4, 8, 9) , Jeannette Chloe Bulinski (3, 10, 4) , Morgane Rousselot (5) , Melanie Simoes Eugenio (11, 5) , Marie-Thérèse Dimanche-Boitrel (11, 12) , Jacobus P. Petzer (13) , Lesetja J. Legoabe (13) , Stéphane Bach (3, 13, 4, 8, 9)

1 UNICAL - University of Calabar
2 Kaduna State University
3 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins
4 SBR - Station biologique de Roscoff = Roscoff Marine Station
5 SeaBeLife Biotech
6 University of Ilorin [Ilorin, Nigeria]
7 University of Uyo
8 KISSf - Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility
9 FR2424 - Fédération de recherche de Roscoff
10 Columbia University [New York]
11 Irset - Institut de recherche en santé, environnement et travail
12 SFR UMS CNRS 3480 - INSERM 018 - Biosit : biologie, santé, innovation technologique
13 NWU - North-West University [South Aftrica]

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from 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.

Mots clés: protein kinase inhibitors; polypharmacology; triterpenoids; Acacia stem bark

Domaines: Sciences du Vivant [q-bio]

Augustine A. Ahmadu, Claire Delehouze, Anas Haruna, Lukman Mustapha, Bilqis A. Lawal, et al.. Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor. Molecules, 2021, 26 (15), pp.4599. ⟨10.3390/molecules26154599⟩. ⟨hal-03331756⟩