Activity of the potent dual Abl/Src tyrosine kinase inhibitor FB2 against Bcr-Abl positive cell lines in vitro and in vivo.
We have previously shown the inhibition of the small-molecule inhibitor FB2 on imatinib-sensitive and resistance CML cell lines with the wild-type Bcr-Abl fusion gene. Here we report the potent and selective antiproliferation on FB2 on transfected Ba/F3 p210 cell lines expressing various isoforms of Bcr-Abl (wild-type, Y253F, T315I). FB2 which orients Bcr-Abl and Src kinase activities, is shown to override imatinib-resistance CML involving Y253F mutation in the Abl kinase domain of the fusion protein except T315I in vivo and in vitro. Thus, we present FB2 that displays potency toward Bcr-Abl and Src as the molecular target, and which could potentially be used to override drug resistance in CML.
Yuan
Xia
X
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Zhang
Yi
Y
Zhang
Haijing
H
Jin
Jing
J
Li
Xiangyan
X
Liu
He
H
Feng
Zhiqiang
Z
Chen
Xiaoguang
X
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; C556348:FB2 compound; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases