title: Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC).
abstract: 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.
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea; Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.affiliation: Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Hee Baek
authors.initials: HB
authors.lastname: Park
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Jang
authors.affiliation: Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, South Korea; Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea. Electronic address: seoyho@kmu.ac.kr.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Seo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins
keywords: Gefitinib resistance; Hsp90; Inhibitor; Lung cancer; Rational design