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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90
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Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

机译：17-烯丙氨基-17-去甲氧基格尔德霉素氢醌盐酸盐（IPI-504）的开发，一种针对Hsp90的抗癌药

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摘要

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.
机译：热休克蛋白90（Hsp90）是治疗癌症的新兴治疗靶标。它在蛋白质稳态和关键信号蛋白在癌症存活和增殖途径中的选择性陪伴中的作用使其成为小分子治疗干预的有吸引力的靶标。研究最多的针对Hsp90的药物17-烯丙基氨基-17-脱甲氧基格尔德霉素（17-AAG）的理化性质不佳，限制了其临床潜力。因此，需要用于临床研究的新颖的，对患者友好的Hsp90指导的药物。合成了IPI-504，它是17-AAG的高度可溶性氢醌盐酸盐衍生物，是具有良好药物特性的Hsp90抑制剂。在Hsp90结合测定以及癌细胞测定中分析了其生化和生物学活性。此外，将IPI-504的代谢谱与目前在临床试验中的格尔​​德霉素类似物17-AAG的代谢谱进行了比较。在骨髓瘤细胞系和体内异种移植模型中，测试了IPI-504的抗肿瘤活性（作为单一药物以及与硼替佐米联用），并确定了IPI-504在肿瘤组织中的保留率。总之，Hsp90的有效抑制剂IPI-504在骨髓瘤的细胞和动物模型中有效。它与蛋白酶体抑制剂硼替佐米具有协同作用，相对于血浆优先保留在肿瘤组织中。重要的是，观察到IPI-504在体外和体内通过氧化还原平衡与已知试剂17-AAG相互转化，并且我们证明IPI-504是Hsp90的强效抑制剂。

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