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Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor.
Ahmadu, Augustine A; Delehouzé, Claire; Haruna, Anas; Mustapha, Lukman; Lawal, Bilqis A; Udobre, Aniefiok; Baratte, Blandine; Triscornia, Camilla; Autret, Axelle; Robert, Thomas; Bulinski, Jeannette Chloë; Rousselot, Morgane; Simoes Eugénio, Mélanie; Dimanche-Boitrel, Marie-Thérèse; Petzer, Jacobus P; Legoabe, Lesetja J; Bach, Stéphane.
Afiliação
  • Ahmadu AA; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Kaduna State University, Kaduna 800241, Nigeria.
  • Delehouzé C; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, University of Calabar, Calabar 540271, Nigeria.
  • Haruna A; Station Biologique de Roscoff, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Sorbonne Université, 29680 Roscoff, France.
  • Mustapha L; Place Georges Teissier, SeaBeLife Biotech, 29680 Roscoff, France.
  • Lawal BA; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Kaduna State University, Kaduna 800241, Nigeria.
  • Udobre A; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Kaduna State University, Kaduna 800241, Nigeria.
  • Baratte B; Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin 240003, Nigeria.
  • Triscornia C; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, University of Uyo, Uyo 520003, Nigeria.
  • Autret A; Station Biologique de Roscoff, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Sorbonne Université, 29680 Roscoff, France.
  • Robert T; CNRS, FR2424, Station Biologique de Roscoff, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Sorbonne Université, 29680 Roscoff, France.
  • Bulinski JC; Station Biologique de Roscoff, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Sorbonne Université, 29680 Roscoff, France.
  • Rousselot M; Place Georges Teissier, SeaBeLife Biotech, 29680 Roscoff, France.
  • Simoes Eugénio M; Station Biologique de Roscoff, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Sorbonne Université, 29680 Roscoff, France.
  • Dimanche-Boitrel MT; CNRS, FR2424, Station Biologique de Roscoff, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Sorbonne Université, 29680 Roscoff, France.
  • Petzer JP; Station Biologique de Roscoff, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Sorbonne Université, 29680 Roscoff, France.
  • Legoabe LJ; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Bach S; Place Georges Teissier, SeaBeLife Biotech, 29680 Roscoff, France.
Molecules ; 26(15)2021 Jul 29.
Article em En | MEDLINE | ID: mdl-34361750
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/ß (GSK-3 α/ß), 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.
Assuntos
Acacia/química; Antineoplásicos Fitogênicos/farmacologia; Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos; Inibidores de Proteínas Quinases/farmacologia; Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores; Triterpenos/farmacologia; Antineoplásicos Fitogênicos/química; Antineoplásicos Fitogênicos/isolamento & purificação; Apoptose/efeitos dos fármacos; Apoptose/genética; Sítios de Ligação; Caseína Quinase 1 épsilon/antagonistas & inibidores; Caseína Quinase 1 épsilon/genética; Caseína Quinase 1 épsilon/metabolismo; Proliferação de Células/efeitos dos fármacos; Proteínas de Fusão bcr-abl/antagonistas & inibidores; Proteínas de Fusão bcr-abl/genética; Proteínas de Fusão bcr-abl/metabolismo; Quinase 3 da Glicogênio Sintase/antagonistas & inibidores; Quinase 3 da Glicogênio Sintase/genética; Quinase 3 da Glicogênio Sintase/metabolismo; Humanos; Janus Quinase 3/antagonistas & inibidores; Janus Quinase 3/genética; Janus Quinase 3/metabolismo; Células K562; Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores; Proteína Quinase 1 Ativada por Mitógeno/genética; Proteína Quinase 1 Ativada por Mitógeno/metabolismo; Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores; Proteína Quinase 3 Ativada por Mitógeno/genética; Proteína Quinase 3 Ativada por Mitógeno/metabolismo; Modelos Moleculares; Quinases Relacionadas a NIMA/antagonistas & inibidores; Quinases Relacionadas a NIMA/genética; Quinases Relacionadas a NIMA/metabolismo; Casca de Planta/química; Extratos Vegetais/química; Ligação Proteica; Conformação Proteica; Inibidores de Proteínas Quinases/química; Inibidores de Proteínas Quinases/isolamento & purificação; Proteínas Proto-Oncogênicas c-abl/química; Proteínas Proto-Oncogênicas c-abl/genética; Proteínas Proto-Oncogênicas c-abl/metabolismo; Transdução de Sinais; Triterpenos/química; Triterpenos/isolamento & purificação; Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores; Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética; Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triterpenos / Regulação Leucêmica da Expressão Gênica / Proteínas Proto-Oncogênicas c-abl / Inibidores de Proteínas Quinases / Acacia / Antineoplásicos Fitogênicos Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triterpenos / Regulação Leucêmica da Expressão Gênica / Proteínas Proto-Oncogênicas c-abl / Inibidores de Proteínas Quinases / Acacia / Antineoplásicos Fitogênicos Idioma: En Ano de publicação: 2021 Tipo de documento: Article