Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its “undruggable” nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesirable labile hydrazone linker and a potentially nonfunctional furazanopyrazine ring that we attempted to eliminate in this study. We found one compound, 7I, that is more active than the parent compound, LQZ-7, and when given orally effectively inhibits xenograft tumor growth and induces survivin loss in tumors. These findings indicate that 7I with a stable linker and a quinoxaline ring can be used as a lead for further optimization of this novel class of survivin inhibitors.

中文翻译：

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蛋白酶体依赖性降解的靶向Survivin二聚体的新型铅的合成和鉴定。

Survivin是凋亡蛋白（IAP）抑制剂家族的同型二聚体成员，是癌细胞生存所必需的，并且在几乎所有实体瘤中均过表达。然而，靶向survivin由于其“非药物”性质而具有挑战性。最近，我们使用了一种新颖的方法来靶向二聚体界面，并鉴定了两个可以直接结合并抑制survivin二聚体的支架的抑制剂。由化合物LQZ-7代表的一种支架包含一个不希望的不稳定link连接子和一个潜在的无功能呋喃并吡嗪环，我们在本研究中尝试消除了这种环。我们发现一种化合物7I，它比母体化合物LQZ-7更具活性，并且口服给予后，可有效抑制异种移植肿瘤的生长并诱导肿瘤中生存素的损失。这些发现表明，具有稳定的连接子和喹喔啉环的7I可以用作进一步优化这种新型survivin抑制剂的线索。