title: Oleylamine-carbonyl-valinol inhibits auto-phosphorylation activity of native and T315I mutated Bcr-Abl, and exhibits selectivity towards oncogenic Bcr-Abl in SupB15 ALL cell lines.
abstract: Chronic myeloid leukemia (CML) is characterized by the presence of p210(Bcr-Abl) which exhibits an abnormal kinase activity. Selective Abl kinase inhibitors have been successfully established for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance against these kinase inhibitors mainly due to point mutations within the Abl protein kinase domain. Previously, we have identified oleic acid as the active component in the mushroom Daedalea gibbosa that inhibited the kinase activity of Bcr-Abl. Here, we report that the oleyl amine derivatives, S-1-(1-Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylaminocarbonyl-L-N-valinol,oroleylaminocarbonyl-S-2-isopropyl-N-ethanolamine,oleylamine-carbonyl-L-valinol] (cpd 6) and R-1-(1-Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylamineocarbonyl-D-N-valinol, oleylaminocarbonyl-R-2-isopropyl-N-ethanolamine, or oleylamine-carbonyl-D-valinol] (cpd 7), inhibited the activity of the native and T315I mutated Bcr-Abl. Furthermore, cpd 6 and 7 exhibited higher activity towards the oncogenic Bcr-Abl in comparison to native c-Abl in SupB15 Ph-positive ALL cell line.
authors.affiliation: Anticancer Drugs Research Lab, Faculty of Pharmacy, Al-Quds University, Jerusalem-Abu Dies, P.O. Box 20002, Palestine.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Hazem
authors.initials: H
authors.lastname: Khamaisie
authors.forename: Nili
authors.initials: N
authors.lastname: Ruimi
authors.forename: Soliman
authors.initials: S
authors.lastname: Khatib
authors.forename: Joshua
authors.initials: J
authors.lastname: Katzhendler
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
authors.forename: Jamal
authors.initials: J
authors.lastname: Mahajna
mesh_terms: D000588:Amines / Q000737:chemistry; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; C040994:valinol; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D014633:Valine; C008703:oleylamine