title: STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer.
abstract: STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta Pharmaceuticals for the intravenous treatment of hematological and solid malignancies. It is a resorcinol-containing triazole compound, with a novel chemical structure that is unrelated to the geldanamycin class of Hsp90 inhibitors. STA-9090 binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and Wilms' tumor 1. STA-9090, at low nanomolar concentrations, potently arrested cell proliferation and induced apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Moreover, administration of STA-9090 led to significant tumor shrinkage in several tumor xenograft models in mice and appeared to be less toxic. Furthermore STA-9090 demonstrated better tumor penetration compared with tanespimycin. In initial phase I clinical trials, STA-9090 was well tolerated and has demonstrated activity. The further development of this agent, and the other Hsp90 inhibitors, may be dependent on the tumor type and the primary oncogenic driving forces.
authors.affiliation: Center for Cancer Research, Medical Oncology Branch & Urologic Oncology Branch, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Wang
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Neckers
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles