title: Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC).
abstract: 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.
authors: College of Pharmacy, Keimyung University, Daegu, 704-701, Korea.
authors: Ju Hui
authors: JH
authors: Jeong
authors: College of Pharmacy, Keimyung University, Daegu, 704-701, Korea.
authors: Yong Jin
authors: YJ
authors: Oh
authors: Department of Immunology, School of Medicine, Keimyung University, Daegu, 704-701, Korea.
authors: Taeg Kyu
authors: TK
authors: Kwon
authors: College of Pharmacy, Keimyung University, Daegu, 704-701, Korea. seoyho@kmu.ac.kr.
authors: Young Ho
authors: http://orcid.org/0000-0002-2268-8761
authors: YH
authors: Seo
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002599:Chalcone / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D062105:Molecular Docking Simulation / Q000379:methods; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011799:Quinazolines; D002599:Chalcone; D000077156:Gefitinib
keywords: Cancer; Chalcone; Gefitinib; Heat shock protein 90; Resistance