title: Natural-Based Indirubins Display Potent Cytotoxicity toward Wild-Type and T315I-Resistant Leukemia Cell Lines.
abstract: Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 μM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both c-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue 22 exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue 22 is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gaboriaud-Kolar
authors.forename: Vasillios
authors.initials: V
authors.lastname: Myrianthopoulos
authors.forename: Konstantina
authors.initials: K
authors.lastname: Vougogiannopoulou
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Gerolymatos
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center , 1500 East Duarte Road, Duarte, California 91010, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Horne
authors.affiliation: Cell Therapy Institute, Nova Southeastern University , 3301 College Avenue, Fort Lauderdale, Florida 33314, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center , 1500 East Duarte Road, Duarte, California 91010, United States.
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015394:Molecular Structure; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C027185:indirubin