Cowan-Jacob Sandra W, Fendrich Gabriele, Floersheimer Andreas, Furet Pascal, Liebetanz Janis, Rummel Gabriele, Rheinberger Paul, Centeleghe Mario, Fabbro Doriano, Manley Paul W
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):80-93. doi: 10.1107/S0907444906047287. Epub 2006 Dec 13.
Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.
慢性粒细胞白血病（CML）由Bcr-Abl癌蛋白引起，该蛋白具有组成型激活的Abl酪氨酸激酶结构域。尽管大多数接受伊马替尼一线治疗的慢性期CML患者保持了良好的持久反应，但进展为晚期CML的患者常常由于该蛋白耐药突变体的出现而对治疗无反应或失去反应。在伊马替尼耐药患者中已观察到40多种此类点突变。测定了野生型和突变型Abl激酶与伊马替尼及其他小分子Abl抑制剂复合物的晶体结构，目的是了解耐药的分子基础，并有助于设计和优化对耐药突变体有活性的抑制剂。这些结果以一种方式呈现，展示了用于生成多个结构的方法、可获得的信息类型以及该信息用于支持药物发现的方式。
