Potentials of Hsp90 Inhibitors in Cancer Therapy
Posted: Jun 20, 2018
To find an ultimate cure for cancer, generations of scientists have devoted tremendous passion and efforts to this great cause. Along this journey, different thinking patterns are explored, and numerous potential targets are tried and tested. Among them, Hsp90 inhibitors have become the center of focus in drug discovery and development ever since its emergence in the past decade. 17-AAG is the first-in-class HSP90 inhibitor that entered into Phase I clinical trial in 1999.
What are Hsp90 inhibitors?
As a molecular chaperone, Hsp90 plays a key role in the conformational maturation of oncogenic signaling proteins. It’s important because it stabilizes a variety of proteins required for survival of cancer cells.
What is the MOA of Hsp90 inhibitors in cancer treatment?
The reason why Hsp90 inhibitors have been developed for cancer treatment is that: inhibiting of the Hsp90 protein folding machinery can lead to simultaneous disruption of multiple oncogenic pathways, which thus prohibits malignant growth and proliferation and finally achieves the aim of killing cancer cells. In addition, Hsp90 inhibitors can be combined with immunotherapy to achieve better effect due to the fact that many patients fail to respond to the promising treatments for cancer patients - T-cell-based immunotherapies.
A study was carried out where 850 bioactive compounds were screened to assess their effect on killing of primary melanoma cell lines by autologous T cells. And the results showed that Hsp90 inhibitors stood out for their ability to synergistically improve T-cell killing. Further analysis followed by proves that the credit should be given to upregulation of interferon response genes.
In general, Hsp90 inhibitors, first of all, have been exploited for their cytotoxic effects on tumor cells, and later on some in vivo studies have raised the possibility of combining Hsp90 inhibitor treatments with immunotherapy so as to create better anti-tumor immune response.
Hsp90 inhibitors and Alzheimer’s disease
Currently there is no effective treatment for Alzheimer's disease which is characterized by the accumulation of hyperphosphorylated tau and? amyloid. Protein misfolding and aggregation is generally viewed as a potential cause of neurodegenerative diseases in that they further leads to neurotoxicity. Recent studies provide a clue that targeting Hsp90 might be an attractive strategy to halt neurodegenerative diseases, which is definitely great news for people with Alzheimer's. Some Hsp90 inhibitors like geldanamycin (GA) and 17-(allylamino)-17-demethoxygeldanamycin have been proved to be beneficial in mutant A53T?-synuclein models. Hsp90 can regulate tau metabolism and A? processing by forming macromolecular complexes with co-chaperones. Although positive signs of small molecule inhibitors of Hsp90 for treating Alzheimer's are shown, there is still a long way to go before they are developed into drugs and enter the market.
The author is a true follower of biochemistry. BOC Sciences, the company he works for, is a trustworthy supplier of inhibitors.