title: Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells.
abstract: Anticancer properties of chemically synthesized compounds have continuously been optimized for better efficacy and selectivity. Derivatives of heterocyclic compounds are well known to have selective antiproliferative effect against many types of cancer. In this study, we investigated the ability of an indigenously synthesized anticancer molecule, G-11 [1-(2",3",4",6"-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3'-trifluoromethylphenylhydrazono)-3-trifluoromethyl-1,4-dihydropyrazol-5-one], to cause selective cytotoxicity and induce differentiation in the acute myeloid leukemia HL-60 cells. G-11 was able to exert cytotoxic effect on hematological (Jurkat, U937, K562, HL-60, CCRF-SB) and solid tumor (MCF-7, HepG2, HeLa, Caco-2) cell lines, with IC50 values significantly lower than noncancerous cells (HEK-293, BJ and Vero) and normal peripheral blood mononuclear cells. G-11 induced differentiation of HL-60 cells to granulocytes and monocytes/macrophages by inhibiting the activation of FLT3 (CD135 tyrosine kinase). ITD-FLT3 mutation found in many acute myeloid leukemia patients could also be targeted by G-11 as exhibited by its inhibitory effect on MOLM-13 and MV4-11 cell lines. Molecular docking studies suggest the involvement of Leu616, Asp698, Cys694 and Cys828 residues in binding of G-11 to FLT3. The ability of G-11 to cause selective cytotoxicity and induce differentiation in cancer cells could be clinically relevant for therapeutic gains.
authors.affiliation: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Mail Code 6610, P. O. Box 9515, Jeddah 21423, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City, National Guard Health Affairs, P. O. Box 9515, Jeddah 21423, Saudi Arabia. Electronic address: salehay@ksau-hs.edu.sa.
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Saleh
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
authors.affiliation: King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Aziz
authors.affiliation: Department of Chemistry, Faculty of Sciences, Yarmouk University, Irbid, Jordan.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Al-Qudah
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
authors.forename: Reem F
authors.initials: RF
authors.lastname: AbuTayeh
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL 33328, United States.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Rizvi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000737:chemistry; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis* / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia (AML); Anticancer; Cell differentiation; FLT3; Heterocyclic compound; Trifluoromethyl-substituted pyrazole N-nucleosides