Oncology, IMED Biotech Unit, AstraZeneca Boston, USA.
Oncology, IMED Biotech Unit, AstraZeneca Boston, USA.
Pharmacol Ther. 2019 Jun;198:59-67. doi: 10.1016/j.pharmthera.2019.02.007. Epub 2019 Feb 18.
Dysregulation of the mitochondrial apoptotic pathway controlled by members of the Bcl-2 protein family plays a central role in cancer development and resistance to conventional cytotoxic as well as targeted therapies. Hence, selective inhibition of pro-survival Bcl-2 family of proteins to activate apoptosis in malignant cells represents an exciting anti-cancer strategy. The remarkable clinical performance of the selective Bcl-2 antagonist venetoclax has highlighted the potential for selective inhibitors of the other pro-survival members of the Bcl-2 family, particularly Mcl-1. Here we review the latest progress on the discovery and development of selective inhibitors of Mcl-1 that are undergoing clinical evaluation for cancer therapy.
Bcl-2 蛋白家族成员调控的线粒体凋亡途径失调在癌症的发生和对传统细胞毒性药物及靶向治疗的耐药中起核心作用。因此，选择性抑制抗凋亡 Bcl-2 家族蛋白以在恶性细胞中激活凋亡代表了一种激动人心的抗癌策略。选择性 Bcl-2 拮抗剂 venetoclax 的显著临床疗效突出了选择性抑制 Bcl-2 家族其他抗凋亡成员（尤其是 Mcl-1）的潜力。本文综述了用于癌症治疗的正在临床评估的选择性 Mcl-1 抑制剂的发现和开发的最新进展。
