Heffron Timothy P
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
J Med Chem. 2016 Nov 23;59(22):10030-10066. doi: 10.1021/acs.jmedchem.6b00618. Epub 2016 Aug 3.
In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood-brain barrier (BBB). The high level of expression of efflux transporters (e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside. Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable. This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer.
除了决定成功的肿瘤药物候选物识别的各个因素外，旨在治疗神经癌的药物研发还必须考虑血脑屏障（BBB）的存在。血脑屏障处外排转运蛋白（如P-糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp））的高表达水平限制了许多小分子自由进入神经肿瘤恶性肿瘤所在的大脑。此外，为潜在治疗中枢神经系统（CNS）恶性肿瘤而确定的许多靶点表明，能够穿透血脑屏障到达靶点的激酶抑制剂将是理想的。本观点讨论了神经肿瘤治疗的未满足需求、该领域激酶靶点的吸引力，以及对治疗脑癌感兴趣的激酶临床抑制剂的脑自由渗透情况的已知总结。
