Vogler Meike
Department of Biochemistry, University of Leicester, Henry-Wellcome Building, Lancaster Road, Leicester LE19HN, UK.
Adv Med. 2014;2014:943648. doi: 10.1155/2014/943648. Epub 2014 Aug 27.
Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.
由于抗凋亡BCL2蛋白在细胞凋亡调控中发挥核心作用,它们是开发新型抗癌疗法的极具潜力的靶点。为此,已开发出多种策略来抑制BCL2、BCL-XL、BCL-w和MCL1。虽然血液系统恶性肿瘤的早期临床试验显示BCL2抑制剂具有令人兴奋的单药活性,但实体瘤中的反应有限,这表明在实体瘤中,必须开发不同的策略才能成功地用BCL2抑制剂治疗患者。在这篇综述中,将讨论不同抗凋亡BCL2蛋白的功能及其在实体瘤中的作用。此外,还将对目前靶向这些抗凋亡BCL2蛋白的小分子(如ABT-737、ABT-263、ABT-199、TW-37、沙布托卡克斯、奥巴托卡克斯和MIM1)进行全面分析,包括对任何临床试验结果的讨论。该分析将总结BCL2抑制剂治疗实体瘤的潜力,并揭示在临床应用中利用这些抑制剂的新方法。