GNF 2

GNF 2是一种高选择性的和非ATP竞争性的Bcr-Abl抑制剂，在多种细胞系中其IC50值为100-300 nM。

BCR-ABL基因由BCR和ABL基因融合而成[1]。BCR-ABL提高酪氨酸激酶的产生，在慢性髓细胞性白血病（CML）的发病中起重要作用[2]。

不同于竞争性抑制BCR-ABL激酶活性ATP结合位点的imatinib[3]，GNF-2变构抑制（通过结合ABL的豆蔻酸结合位点[4]）BCR-ABL阳性细胞的增殖并诱导细胞凋亡。在表达Bcr-abl的Ba/F3.p210细胞中，GNF-2处理48小时能够抑制细胞增殖，IC50值为138 nM [5]。此外，GNF-2能够抑制E255V和Y253H突变的Ba/F3细胞生长，IC50值分别为268 nM和194 nM [5]。GNF-2也会抑制K562和SUP-B15的生长，IC50值分别为273 nM和268 nM [5]。

注射表达BCR-ABL的Ba/F3-p210细胞能够诱导外周血中淋巴细胞减少4% [6]。

参考文献：
[1]. REDDY, K. S. & GROVE, B. 1998. A Philadelphia-Negative Chronic Myeloid Leukemia with a BCR/ABL Fusion Gene on Chromosome 9. Cancer Genetics and Cytogenetics, 107, 48-50.
[2]. RUMPOLD, H. & WEBERSINKE, G. 2011. Molecular pathogenesis of Philadelphia-positive chronic myeloid leukemia - is it all BCR-ABL Curr Cancer Drug Targets, 11, 3-19.
[3]. SEGGEWISS, R., LORE, K., GREINER, E., MAGNUSSON, M. K., PRICE, D. A., DOUEK, D. C., DUNBAR, C. E. & WIESTNER, A. 2005. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood, 105, 2473-2479.
[4]. FABBRO, D., MANLEY, P. W., JAHNKE, W., LIEBETANZ, J., SZYTTENHOLM, A., FENDRICH, G., STRAUSS, A., ZHANG, J., GRAY, N. S., ADRIAN, F., WARMUTH, M., PELLE, X., GROTZFELD, R., BERST, F., MARZINZIK, A., COWAN-JACOB, S. W., FURET, P. & MESTAN, J. 2010. Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1804, 454-462.
[5]. ADRIAN, F. J., DING, Q., SIM, T., VELENTZA, A., SLOAN, C., LIU, Y., ZHANG, G., HUR, W., DING, S., MANLEY, P., MESTAN, J., FABBRO, D. & GRAY, N. S. 2006. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol, 2, 95-102.
[6].  ADRIAN, F. J., DING, Q., SIM, T., VELENTZA, A., SLOAN, C., LIU, Y., ZHANG, G., HUR, W., DING, S., MANLEY, P., MESTAN, J., FABBRO, D. & GRAY, N. S. 2006. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol, 2, 95-102.