Genentech, Inc., Department of Medicinal Chemistry, 1 DNA Way, South San Francisco, CA 94080, USA.
Expert Opin Ther Pat. 2010 Feb;20(2):251-67. doi: 10.1517/13543770903567077.
The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival that have become important targets for therapeutic intervention in human malignancies. One strategy for targeting IAP proteins involves agents that mimic the amino terminus of the endogenous IAP protein antagonist second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low pI (DIABLO) and thus block critical IAP protein interactions.
This review of the IAP antagonist patent literature covers the period from 2000 to mid-2009. Over 50 patents and patent applications pertaining to IAP antagonists have been published over the past 10 years. In the case of several filings, only the original source is reviewed in this analysis.
Readers will gain an overview of IAP protein antagonist scaffolds, with representative examples including monovalent and bivalent Smac mimetics, and an understanding of their structure-activity relationships.
The feasibility of disrupting IAP protein interactions with pro-apoptotic proteins using monovalent and bivalent Smac-derived peptidomimetic compounds has been broadly established. Four such compounds have entered or been approved to enter human clinical trials, which will hopefully allow the utility of this potential therapeutic approach to be evaluated in cancer patients.
凋亡抑制蛋白（IAP）是癌细胞生存的关键调节因子，已成为人类恶性肿瘤治疗干预的重要靶点。针对 IAP 蛋白的一种策略涉及到模仿内源性 IAP 蛋白拮抗剂第二线粒体衍生的半胱天冬酶激活剂（Smac）/直接 IAP 结合蛋白低 pI（DIABLO）的氨基末端的试剂，从而阻断关键的 IAP 蛋白相互作用。
本综述涵盖了 IAP 拮抗剂专利文献的时期，从 2000 年到 2009 年年中。在过去的 10 年中，已经发表了 50 多项与 IAP 拮抗剂相关的专利和专利申请。在某些情况下，仅对原始来源进行了分析。
读者将获得 IAP 蛋白拮抗剂支架的概述，包括单价和二价 Smac 模拟物的代表性实例，并了解它们的结构-活性关系。
使用单价和二价 Smac 衍生的肽模拟物化合物来破坏 IAP 蛋白与促凋亡蛋白的相互作用的可行性已经得到广泛证实。其中有四种化合物已经进入或被批准进入人体临床试验，这有望使这种潜在治疗方法在癌症患者中的应用得到评估。
