TY - JOUR
T1 - Targeting the molecular chaperone heat shock protein 90 (HSP90)
T2 - Lessons learned and future directions
AU - Hong, David S.
AU - Banerji, Udai
AU - Tavana, Bahareh
AU - George, Goldy C.
AU - Aaron, Joann
AU - Kurzrock, Razelle
N1 - Funding Information:
Gotkin/Sarnoff Scholarship, Dr. Udai Banerji is supported by Cancer Research UK Programme Grant C309/A8274 and also acknowledges support from the Cancer Research UK and the National Institute for Health Research Experimental Cancer Medicine Centre and for the National Institute for Health Research Biomedical.
PY - 2013/6
Y1 - 2013/6
N2 - Due to the critical role of heat shock protein 90 (HSP90) in regulating the stability, activity and intracellular sorting of its client proteins involved in multiple oncogenic processes, HSP90 inhibitors are promising therapeutic agents for cancer treatment. In cancer cells, HSP90 client proteins play a major role in oncogenic signal transduction (i.e., mutant epidermal growth factor receptor), angiogenesis (i.e., vascular endothelial growth factor), anti-apoptosis (i.e., AKT), and metastasis (i.e., matrix metalloproteinase 2 and CD91), processes central to maintaining the cancer phenotype. Thus, HSP90 has emerged as a viable target for antitumor drug development, and several HSP90 inhibitors have transitioned to clinical trials. HSP90 inhibitors include geldanamycin and its derivatives (i.e., tanespimycin, alvespimycin, IPI-504), synthetic and small molecule inhibitors (i.e., AUY922, AT13387, STA9090, MPC3100), other inhibitors of HSP90 and its isoforms (i.e., shepherdin and 5'-N-ethylcarboxamideadenosine). With more than 200 "client" proteins, many of them meta-stable and oncogenic, HSP90 inhibition can affect an array of tumors. Here we review the molecular structure of HSP90, structural features of HSP90 inhibition, pharmacodynamic effects and tumor responses in clinical trials of HSP90 inhibitors. We also discuss lessons learned from completed clinical trials of HSP90 inhibitors, and future directions for these promising therapeutic agents.
AB - Due to the critical role of heat shock protein 90 (HSP90) in regulating the stability, activity and intracellular sorting of its client proteins involved in multiple oncogenic processes, HSP90 inhibitors are promising therapeutic agents for cancer treatment. In cancer cells, HSP90 client proteins play a major role in oncogenic signal transduction (i.e., mutant epidermal growth factor receptor), angiogenesis (i.e., vascular endothelial growth factor), anti-apoptosis (i.e., AKT), and metastasis (i.e., matrix metalloproteinase 2 and CD91), processes central to maintaining the cancer phenotype. Thus, HSP90 has emerged as a viable target for antitumor drug development, and several HSP90 inhibitors have transitioned to clinical trials. HSP90 inhibitors include geldanamycin and its derivatives (i.e., tanespimycin, alvespimycin, IPI-504), synthetic and small molecule inhibitors (i.e., AUY922, AT13387, STA9090, MPC3100), other inhibitors of HSP90 and its isoforms (i.e., shepherdin and 5'-N-ethylcarboxamideadenosine). With more than 200 "client" proteins, many of them meta-stable and oncogenic, HSP90 inhibition can affect an array of tumors. Here we review the molecular structure of HSP90, structural features of HSP90 inhibition, pharmacodynamic effects and tumor responses in clinical trials of HSP90 inhibitors. We also discuss lessons learned from completed clinical trials of HSP90 inhibitors, and future directions for these promising therapeutic agents.
KW - HSP90
KW - HSP90 inhibitors
KW - Molecular chaperone
KW - Molecularly targeted therapy
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U2 - 10.1016/j.ctrv.2012.10.001
DO - 10.1016/j.ctrv.2012.10.001
M3 - Review article
C2 - 23199899
AN - SCOPUS:84875519144
SN - 0305-7372
VL - 39
SP - 375
EP - 387
JO - Cancer treatment reviews
JF - Cancer treatment reviews
IS - 4
ER -