Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor.

中文翻译：

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Paralog特异性决定TRAP1抑制剂的亚细胞分布，作用机制和抗癌活性

尽管Hsp90抑制剂可以抑制癌细胞中的多种致瘤途径，但其抗癌活性一直令人失望。但是，通过使用线粒体递送载体将Hsp90抑制剂强迫进入线粒体，它们被转化为靶向线粒体Hsp90旁系同源物TRAP1的有效药物。在这里，为了在不使用线粒体递送载体的情况下改善线粒体药物的积累，我们通过减少药物与丰富的细胞质Hsp90的结合来增加细胞质中可自由利用的药物浓度。分析X射线共晶体结构后，将Hsp90抑制剂2（BIIB021）的嘌呤环修饰为吡唑并嘧啶骨架。一种吡唑并嘧啶，12b（DN401）与TRAP1的结合优于与Hsp90的结合，可在体内灭活线粒体TRAP1，并表现出强大的抗癌活性。因此，开发12b的基本原理和可行指南可潜在地用于设计有效的TRAP1抑制剂。