Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Leuk Res. 2011 Feb;35(2):237-42. doi: 10.1016/j.leukres.2010.07.041. Epub 2010 Aug 23.
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.
我们之前已经证明了小分子抑制剂 FB2 对具有野生型 Bcr-Abl 融合基因的伊马替尼敏感和耐药 CML 细胞系的抑制作用。在这里，我们报告了 FB2 对转染的 Ba/F3 p210 细胞系的有效且选择性的增殖抑制作用，这些细胞系表达各种形式的 Bcr-Abl（野生型、Y253F、T315I）。FB2 使 Bcr-Abl 和Src 激酶活性定向，表明它可以克服体内和体外涉及融合蛋白 Abl 激酶结构域中 Y253F 突变的伊马替尼耐药 CML，但不能克服 T315I。因此，我们提出了 FB2，它显示出对 Bcr-Abl 和 Src 的效力作为分子靶标，并有可能用于克服 CML 的耐药性。
