Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC).

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.