期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1823, 期 3, 页码 742-755出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2011.10.008
关键词
Heat shock protein 90; Chaperone; Cancer; Targeted therapy
资金
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center
- Geoffrey Beene Cancer Research Center of MSKCC
- Leukemia and Lymphoma Society
- Cancer Research Fund
- SPORE
- Hirshberg Foundation for Pancreatic Cancer
- National Institutes of Health [1U01 AG03296901A1, 1R01 CA155226-01, 1R21A1090501-01, 3P30CA008748]
- Department of Defense [R03-BC085588, PDF-BC093421]
- Institute for the Study of Aging
- Association for Frontotemporal Dementias (AFTD) [281207]
- Conquer Cancer Foundation
- ASCO Cancer Foundation/Breast Cancer Research Foundation
- Byrne Fund
- Breast Cancer Research Fund
Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90). (C) 2011 Elsevier B.V. All rights reserved.
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