Hird Alexander W, Aquila Brian M, Hennessy Edward J, Vasbinder Melissa M, Yang Bin
AstraZeneca, Medicinal Chemistry, Oncology iMed , 35 Gatehouse Drive, Waltham, MA 02451 , USA +1 781 839 4145 ;
Expert Opin Ther Pat. 2015 Jul;25(7):755-74. doi: 10.1517/13543776.2015.1041922. Epub 2015 May 18.
The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.
This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists.
In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space - for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles - tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.
凋亡抑制蛋白（IAP）家族在抑制促凋亡信号传导中起关键作用；因此，一种能破坏IAP与其功能伙伴结合的小分子应能恢复细胞对促凋亡刺激的凋亡反应。在过去4年中，IAP拮抗剂新专利申请的持续发布证明了人们对IAP蛋白家族的持续关注。
本综述总结了2010年至2014年的IAP拮抗剂专利文献。将涵盖单价和双价Smac模拟物，以及该领域的两项新进展：与其他靶向药物偶联或融合的IAP拮抗剂和新型BIR2选择性IAP拮抗剂。
除了对单价和双价Smac模拟物进行充分探索的支架外，一些公司采取了更激进的方法来探索新的化学空间——例如基于片段的方法和大环抑制剂。此外，其他公司设计了具有替代生物学特性的化合物——与已知激酶结合结构相连，试图靶向线粒体或引入对BIR2结构域的选择性结合。还提供了正在进行的人体临床试验中评估的四种小分子IAP拮抗剂的现状概述。
