生物活性

• 靶点	HSP90 IC50:18nM

• 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. Onalespib is a potent HSP90 inhibitor with Kd value of 0.71nM. Treatment with Onalespib led to the down-regulation of the oncogenic client proteins Raf-1 and CDK4 at concentration around 30nM, as well as growth inhibition with IC50 value of 48nM in HCT116 cells. The up-regulation of Hsp70 can be observed at concentration>10nM, which was regarded as a biomarker readout for Hsp90 inhibition. Intraperitoneal injection with the L-lactate salt form of Onalespib at dose of 60mg/kg per day for 3 days on and 3 days off for four cycles caused tumor growth inhibition by 78% in HCT116nhuman colon cancer xenografts and a tumor growth delay of 17 days after cessation of dosing^[1].
• 作用机制Onalespib can bind in the ATPase binding site of HSP90.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A231 cells	-	Proliferation assay	48 h	Antiproliferative activity against human A231 cells after 48 hrs by MTT assay, IC50=1.01 μM	24763261
  human HCT116 cells	-	Cytotoxic assay	-	Cytotoxicity against human HCT116 cells by Alamar blue assay, IC50=0.048 μM	20662534
  human HCT116 cells	-	Proliferation assay	48 h	Antiproliferative activity against human HCT116 cells after 48 hrs by MTT assay, IC50=0.08 μM	24763261

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• 动物研究
  剂量	Mice: 55 mg/kg weekly[2] (i.p.), 80 mg/kg[3] (i.p.), 30 mg/kg[4] (i.v.)
  给药途径	i.p., i.v.
  动物药代数据	Animal Mice[1] Administration i.v. CL 113 - 200 ml/min/kg T1/2 0.9 - 3.2 h Vd 11 - 13 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
  NCT01685268	Prostate Cancer	Phase 1 Phase 2	Completed	-	-
  NCT02474173	Estrogen Receptor Negative ... more >> HER2/Neu Negative Progesterone Receptor Negative Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7 Triple-Negative Breast Carcinoma Collapse <<	Phase 1	Recruiting	-	United States, Kentucky ... more >> University of Kentucky/Markey Cancer Center Recruiting Lexington, Kentucky, United States, 40536 Contact: Site Public Contact    859-257-3379       Principal Investigator: Mara D. Chambers          United States, Ohio Ohio State University Comprehensive Cancer Center Recruiting Columbus, Ohio, United States, 43210 Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu    Principal Investigator: Robert Wesolowski          United States, Pennsylvania Thomas Jefferson University Hospital Recruiting Philadelphia, Pennsylvania, United States, 19107 Contact: Site Public Contact    215-955-6084       Principal Investigator: Saveri Bhattacharya          University of Pittsburgh Cancer Institute (UPCI) Recruiting Pittsburgh, Pennsylvania, United States, 15232 Contact: Site Public Contact    412-647-8073       Principal Investigator: Adam M. Brufsky Collapse <<
  NCT02381535	Stage III Hypopharyngeal Squam... more >>ous Cell Carcinoma AJCC v7 Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7 Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7 Collapse <<	Phase 1	Active, not recruiting	-	United States, Connecticut ... more >> Yale University New Haven, Connecticut, United States, 06520 Canada, Ontario University Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<

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