Eck Michael J, Manley Paul W
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Curr Opin Cell Biol. 2009 Apr;21(2):288-95. doi: 10.1016/j.ceb.2009.01.014. Epub 2009 Feb 11.
As an inhibitor of the tyrosine kinase activity of the BCR-Abl oncoprotein, imatinib sets a new paradigm for the treatment of cancer with molecularly targeted therapies. Subsequent structural studies have provided in depth knowledge of how this antileukaemia drug interacts with the catalytic site of the enzyme and allowed the rationalisation of mechanisms of drug-resistance which can lead to patient relapse. This understanding has facilitated the design of new inhibitors of BCR-Abl, as well as the discovery of inhibitors of many other kinases. As structural information accumulates for more of the 518 kinases encoded within the human genome, the design of many more highly selective, well-tolerated kinase inhibitors should be possible.
作为BCR-Abl癌蛋白酪氨酸激酶活性的抑制剂，伊马替尼为分子靶向治疗癌症树立了新的典范。随后的结构研究深入揭示了这种抗白血病药物如何与该酶的催化位点相互作用，并使导致患者复发的耐药机制合理化。这种认识推动了新型BCR-Abl抑制剂的设计，以及许多其他激酶抑制剂的发现。随着人类基因组中编码的518种激酶中越来越多的激酶积累了结构信息，设计出更多高选择性、耐受性良好的激酶抑制剂应该是可行的。
