生物活性

• 靶点	HSP90 Kd:1.2μM

• 描述HSP90 (heat shock protein 90) is a cellular ubiquitous molecular chaperone responsible for promoting the conformational mutation and stabilization of several client oncoproteins, including Met, B-Raf, p53, Akt, and Kit, function of which is required by tumor cells to maintain appropriate client protein expression necessary for proliferation and survival. Geldanamycin is the first class of HSP90 inhibitor with a Kd value of 1.2 µM and IC50<2μM for ATPase activity of Hsp90^[1]. Treatment with geldanamycin at concentration of 0.5μM or 1μM for 24h reduced the protein level of AKT, as well as Raf-1 and its downstream p-MEK1/2, but not N-Ras or MEK1/2 in SH-SY5Y cells. Geldanamycin at concentration of 1μM for 48h could induce apoptosis in several neuroblastoma cell lines, including SH-SY5Y, SK-N-SH and LAN-1 cells^[2]. Intraperitoneal administration of geldanamycin (10 mg/kg) ameliorated ICH-induced increase of brain water content significantly, improved the neurological outcome and had a neuroprotective effect after ICH^[3].
• 作用机制Geldanamycin can bind to the N-terminal ATP/ADP-binding domain of Hsp90 and minhibit the inherent ATPase activity of Hsp90.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cells	-	Proliferation assay	-	Compound was evaluated for antiproliferative activity against human ovarian carcinoma cell line A2780, IC50=3.4 μM	11514145
  HCT116 cells	-	Proliferation assay	-	Antiproliferative activity against human HCT116 cells by luminescence assay, EC50=0.03 μM	21605975
  HEK293T cells	-	Function assay	-	Inhibition of TNF-alpha-induced NF-kappaB activation expressed in HEK293T cells by luciferase reporter gene assay	18408713

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• 动物研究
  剂量	Mice: 5 mg/kg - 20 mg/kg[4] (i.p.), 0.1 mg/kg - 1 mg/kg[5] (intraplantar)
  给药途径	i.p., intraplantar
  动物药代数据	Animal Mice[6] Dogs[6] Administration i.v. i.v. MRT 20.7 min 46.6 min Vz 4.11 L/kg Vz/F 3.81 L/kg CL 30.5 ml/min/kg 49.4 ml/min/kg Vss 0.68 L/kg 2.31 L/kg

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01193491	Hematologic Malignancies	Phase 1	Terminated(Drug exposure of re... more >>taspimycin HCl was superior to IPI-493, Infinity will focus on Retaspimycin HCL) Collapse <<	-	United States, Maryland ... more >> Johns Hopkins Sidney Kimmel Cancer Center Baltimore, Maryland, United States, 21201 United States, New York Weill Cornell Cancer Center New York, New York, United States, 10065 United States, Texas M.D. Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT00319930	Chronic Lymphocytic Leukemia	Phase 1	Terminated(Discontinuation of ... more >>program) Collapse <<	-	United States, Florida ... more >> Ocoee, Florida, United States, 34761 United States, New York Albany, New York, United States, 12208 United States, Ohio Dayton, Ohio, United States, 45409 United States, South Carolina Greenville, South Carolina, United States, 29605 United States, Texas Tyler, Texas, United States, 75702 United States, Virginia Norfolk, Virginia, United States, 85258 Collapse <<
  NCT00093821	Childhood Chronic Myelogenous ... more >>Leukemia Childhood Desmoplastic Small Round Cell Tumor Disseminated Neuroblastoma Metastatic Childhood Soft Tissue Sarcoma Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Metastatic Osteosarcoma Previously Treated Childhood Rhabdomyosarcoma Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Neuroblastoma Recurrent Osteosarcoma Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10065 Collapse <<

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• 参考文献

• [1] Woodhead AJ, Angove H, et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl] methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69.

  [2] Kim S, Kang J, et al. Geldanamycin decreases Raf-1 and Akt levels and induces apoptosis in neuroblastomas. Int J Cancer. 2003 Jan 20;103(3):352-9.

  [3] Manaenko A, Fathali N, et al. Geldanamycin reduced brain injury in mouse model of intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:161-5.

  [4] Kasibhatla SR, Hong K, et al. Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem. 2007 Jun 14;50(12):2767-78. Epub 2007 May 8.

  [5] Bucci M, Roviezzo F, et al. Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo. Br J Pharmacol. 2000 Sep;131(1):13-6.

  [6] Supko JG, Hickman RL, et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995;36(4):305-15.

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