College of Pharmacy, Keimyung University, Daegu 704-701, South Korea; Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
Bioorg Med Chem Lett. 2014 Jan 1;24(1):224-7. doi: 10.1016/j.bmcl.2013.11.034. Epub 2013 Nov 22.
Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein.
热休克蛋白 90（Hsp90）在稳定和成熟许多致癌蛋白方面发挥作用，因此成为有吸引力的癌症治疗靶标。我们采用基于结构的方法，通过连接 VER-49009（2）的间苯二酚环和 PU3（3）的三甲氧基苯基环，设计了一系列混合 Hsp90 抑制剂。随后的测试证实，化合物 1f 抑制吉非替尼耐药 H1975 细胞增殖，导致包括 EGFR、Met、Her2 和 Akt 在内的 Hsp90 客户蛋白降解，并诱导 Hsp70 的表达。本文描述了 1f 的设计、合成和评价。
