Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom; Cyclofluidic Limited, BioPark, Welwyn Garden City AL7 3AX, United Kingdom.
Drug Discov Today. 2013 Oct;18(19-20):992-1000. doi: 10.1016/j.drudis.2013.06.001. Epub 2013 Jun 14.
The story of the inhibition of BCR-ABL as a treatment for chronic myelogenous leukaemia serves to illustrate key aspects of the kinase drug discovery and development process. Firstly, elucidation of the disease mechanism enabled identification of the molecular target(s) which catalysed pharmaceutical research and resulted in Gleevec(®) (Novartis) as the first FDA approved BCR-ABL inhibitor. However, clinical success was soon tempered by the emergence of drug resistance through various mechanisms. Using rational drug design, several hypotheses were devised to overcome resistance issues leading to the development of second generation inhibitors, providing clinicians and patients with greater therapeutic choice.
BCR-ABL 抑制作为慢性髓性白血病的治疗方法的故事阐明了激酶药物发现和开发过程的关键方面。首先，阐明疾病机制使能够鉴定催化药物研究的分子靶标，并导致格列卫（®）（诺华）成为第一个获得 FDA 批准的 BCR-ABL 抑制剂。然而，临床成功很快因通过各种机制出现耐药性而受到影响。通过合理的药物设计，提出了几种假设来克服耐药性问题，从而开发出第二代抑制剂，为临床医生和患者提供了更多的治疗选择。
