title: Structure-based design of flavone-based inhibitors of wild-type and T315I mutant of ABL.
abstract: The existence of drug resistance caused by mutations in the break-point cluster region-Abelson (BCR-ABL) tyrosine kinase domain remains a clinical challenge due to limited treatment options for effective CML therapies. Here, we report a series of flavone-based common inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of BCR-ABL. The original hit 1 was extensively modified through a structure-based drug design strategy, especially by varying the C7 acetamide appendage of the scaffold to exploit extended interactions with P-loop residues. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of ABL are discussed in detail.
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Hyeonjeong
authors.initials: H
authors.lastname: Choe
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D047309:Flavones; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl; C043562:flavone