title: Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives as Potent Pan Bcr-Abl inhibitors including the threonine(315)→isoleucine(315) mutant.
abstract: A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-Abl(WT) and Bcr-Abl(T315I) with IC(50) values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-Abl(WT) or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-Abl(T315I), with IC(50) values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health,  Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Li
authors.forename: Mengjie
authors.initials: M
authors.lastname: Shen
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Pan
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Huoyou
authors.initials: H
authors.lastname: Long
authors.forename: Donghai
authors.initials: D
authors.lastname: Wen
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Leng
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Li
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007532:Isoleucine / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013912:Threonine / Q000235:genetics*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D007532:Isoleucine; D013912:Threonine; C037689:benzamide; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl