AstraZeneca R&D Boston, Waltham, MA 02451, United States.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1690-4. doi: 10.1016/j.bmcl.2011.12.109. Epub 2011 Dec 31.
A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
已经发现了一系列结构独特的 Smac 模拟物，它们可以作为凋亡蛋白抑制剂 (IAPs) 的拮抗剂。虽然大多数之前描述的 Smac 模拟物都包含在 Smac 中发现的脯氨酸环（或类似的环状基序），但本文所描述的化合物的一个关键特征是该环已被去除。尽管如此，该系列中的化合物仍能强烈结合 cIAP1，并在癌细胞中引发预期的 cIAP1 抑制表型。这些化合物对 cIAP1 表现出明显的选择性，优于 XIAP，这归因于两种蛋白质之间结合槽的细微差异以及与抑制剂的空间相互作用。通过限制抑制剂，使这些不利的空间相互作用最小化，可以改善 XIAP 的结合。
