生物活性

• 描述Heat shock protein 90 (Hsp90) is a molecular chaperone protein that stabilizes client oncogenic proteins in breast cancer cells. PU-H71 is a novel Hsp90 inhibitor with an IC50 value of 51nM. The treatment with PU-H71 at a dosage of 1µM resulted in significant cell death in triple-negative breast cancer (TNBC) cell lines MDA-MB-468 (80%), MDA-MB-231 (65%), and HCC-1806 (80%). The inhibition of Hsp90 by PU-H71 (10–1000nM) induced a concentration-dependent inactivation or degradation of tumor driving molecules, including epidermal growth factor receptor, insulin-like growth factor receptor, HER3, and c-Kit. PU-H71 (10–1000nM) also downregulated the proteins related to G₂-M progression, such as cyclin-dependent kinase 1 and checkpoint kinase 1. The treatment of MDA-MB-468 cells with 0.25, 0.5, and 1μM PU-H71 for 24 h increased the percentage of cells in G₂-M phase to 30%, 44%, and 69%, respectively. PU-H71 at 250–1000nM induced apoptosis in TNBC cells by inactivating and downregulating Bcl-xL and Akt. The treatment of MDA-MB-231 cells with 0.5 and 1μM PU-H71 for 24 h reduced the NF-κB activity by 84% and 90%, respectively. In the MDA-MB-231 xenograft mouse model, PU-H71 (75 mg/kg on an alternate day schedule) completely inhibited tumor growth after 37 days of treatment. In the fast growing HCC-1806 tumors, six doses of PU-H71 (75 mg/kg on an alternate day schedule) over a 12 days resulted in an 87% regression in tumor volume.
• 作用机制PU-H71 is a potent inhibitor of Hsp90 both in vitro and in vivo. When Hsp90 is inactivated, many TNBC oncoproteins that form a complex with PU-H71-bound Hsp90 become destabilized and subsequently degraded.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  H69AR cells	-	Function assay	96 h	Inhibition of HSP90-mediated antiapoptotic activity in human H69AR cells assessed as induction of cell growth arrest at 10 after 96 hrs by propidium iodide staining-based flow cytometry	17603540
  MCF7 cells	-	Function assay	24 h	Inhibition of Hsp90 in human MCF7 cells assessed as Her2 level after 24 hrs by Western blot, IC50=0.06 μM	18571929
  MDA-MB-468 cells	-	Function assay	-	Inhibitory activity against Hsp90 in human breast cancer MDA-MB-468 cell line, EC50=0.0102 μM	16392823

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• 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
  NCT01581541	Solid Tumors ... more >>Lymphoma Collapse <<	Phase 1	Terminated(The study closed pr... more >>ematurely due to discontinuation of drug supply.) Collapse <<	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<
  NCT01269593	Non-Hodgkin's Lymphoma ... more >> Myeloma Active Solid Malignancy Collapse <<	Early Phase 1	Recruiting	December 2019	United States, New York ... more >> Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Mark Dunphy, DO    212-639-8131       Contact: Gabriela Chiosis, PhD    646-888-2235       Principal Investigator: Mark Dunphy, DO Collapse <<
  NCT01393509	Metastatic Solid Tumor ... more >> Lymphoma Myeloproliferative Neoplasms (MPN) Collapse <<	Phase 1	Active, not recruiting	July 2019	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] Gallerne C, Prola A, et al. Hsp90 inhibition by PU-H71 induces apoptosis through endoplasmic reticulum stress and mitochondrial pathway in cancer cells and overcomes the resistance conferred by Bcl-2. Biochim Biophys Acta. 2013 Jun;1833(6):1356-66.

  [2] Caldas-Lopes E, Cerchietti L, et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73.