College of Pharmacy, Keimyung University, Daegu, 704-701, Korea.
Department of Immunology, School of Medicine, Keimyung University, Daegu, 704-701, Korea.
Arch Pharm Res. 2017 Jan;40(1):96-105. doi: 10.1007/s12272-016-0848-z. Epub 2016 Oct 21.
The molecular chaperone Hsp90 has emerged as an attractive cancer therapeutic target due to its role in cellular homeostasis by modulating the stabilization and maturation of many oncogenic proteins. In this study, we designed and synthesized a series of Hsp90 inhibitors that hybridized NVP-AUY992 (2) and PU3 (3) in the chalcone scaffold using a structure-based approach. Our results indicate that compound 1g inhibited the proliferation of gefitinib-resistant non-small cell lung cancer (H1975) cells, downregulated the expression of client proteins of Hsp90 including EGFR, MET, Her2 and Akt, and up-regulated the expression of Hsp70. The compound 1g represents a new class of Hsp90 inhibitors with a chalcone structure. The design, synthesis, and evaluation of 1g are described herein.
分子伴侣 Hsp90 因其在调节许多致癌蛋白的稳定和成熟方面在细胞内稳态中的作用，已成为一种有吸引力的癌症治疗靶标。在这项研究中，我们使用基于结构的方法，在查尔酮支架中设计并合成了一系列融合 NVP-AUY992（2）和 PU3（3）的 Hsp90 抑制剂。我们的研究结果表明，化合物 1g 抑制了表皮生长因子受体（EGFR）突变的非小细胞肺癌（H1975）细胞的增殖，下调了 Hsp90 的客户蛋白（包括 EGFR、MET、Her2 和 Akt）的表达，并上调了 Hsp70 的表达。化合物 1g 代表了一类具有查尔酮结构的新型 Hsp90 抑制剂。本文描述了 1g 的设计、合成和评价。
