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HSP90 INHIBITORS AND ONCOGENES

HSP90 CASCADE AND CANCER CELLS:
Hsp90 or the Heat shock protein 90 is a non fibrous protein that gained its name on the basis of its molecular weight i.e., 90 kDa. Heat shock protein 90 is the most abundant protein present in cytoplasm that plays a significant role in the cells by acting as molecular chaperones for different proteins associated with some important signaling pathways in the cells. Various molecular chaperones existing in the cells, involves in the tyrosine kinases and serine/theronine kinases as well, so they are very important for proper regulation of cell cycle and cell growth. A complete research has been done to describe the relation between cancer and Hsp90 [1]. For the inhibition of Hsp90 chaperone a simple strategy is designed i.e., development of Hsp-60 inhibitor in case of presence of Hsp90 in the cancerous cells and activated by the activation of various oncogenes [2]. It was proved to be an efficient therapy for the treatment of cancer.


HSP90 INHIBITORS AND THEIR PHARMACOLOGICAL PROPERTIES:
Various antagonists and agonists of hsp90 were used by different research groups to describe the complex regulatory process of heat shock protein 90 in the normal and neo plastic cells that can be helpful in production of some of the novel and potent hsp90 inhibiting drugs [3]. These chemical agents are not very costly and are also in easy access for the researchers, so they can get them easily from the respective suppliers. Among these inhibitors, many are characterize by utilizing common compound library screening. Cancer cells’ characterization was carried out by different hyperactive pathways for example PI3K, EGFR and AKT etc., hence use of the specific inhibitors of hsp90 pathways can check its function ultimately stimulating the process of apoptotic cell death. A well known example of these inhibitors is Geldamycin and its analogue 17-AAD or 17-allylaminogeldanamycin, PU-H71, PU24FC1, SNX-2112, Rifabutin and Celastrol etc. Among these drugs a majority is specific for heat shock protein 90 while some of them can inhibit the other molecules as well.


CLINICAL TRIALS OF HSP90 INHIBITORS:
Different effects of heat shock protein inhibitors on HSP90 has been observed when these inhibitors were evaluated in various clinical studies as a result further leading to the efficient and effective inhibitors for the cancer therapy. National Cancer Institute or NCI has conducted a clinical trial of SNX-5422 in which solid tumors (NCT00644072) and lymphomas were placed under the in vitro treatment and provided very promising results. Cancerous models of animals were directed with this inhibitor which resulted in the inhibition of ERK and AKT cascades to decrease the proliferation and growth of tumor and the angiogenesis of cancer cells was reported [4]. A chemical agent named Geldamycin is derived from benzoquinone and is the most famous Hsp90 inhibitor and was present in the bacterial strain Streptomyces hygroscopicus [5]. It was also observed that this drug causes the arresting of cell cycle in the MAP kinase independent way [6].  17AAG or -N-Allylamino-17-demethoxygeldanamycin which is a derivative molecule of Geldamycin was used for treatment of leukemia, solid tumors and renal cancer and exhibited good results. Celastrol is another molecule that has gained appreciation during its clinical trials for its property of targeting the cell cycle of monocytic human leukemia at the Go/G1 stage in the irreversible manner [7]. In the same way many other inhibitors are under pre clinical stages and are sure to be called for clinical trials after their effective results.


REFERENCES:
1. Neckers L, e.a., Hsp90 as an anti-cancer target. Drug Resist Updat., 1999.
2. Trepel J, e.a., Targeting the dynamic HSP90 complex in cancer. Nature Reviews Cancer, 2010.
3. Luke Whitesell L, L.S., HSP90 and the Chaperoning of Cancer. Nature Reviews Cancer, 2005.
4. Okawa Y, e.a., SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK Blood, 2005.
5. He W, e.a., Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus. Current Microbiology, 2006.
6. Bedin M, e.a., Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest. Int J Cancer, 2004.
7. Peng B, e.a., HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way. Molecular Cancer, 2010.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S2639 SNX-2112 (PF-04928473) SNX-2112 (PF-04928473) selectively binds to the ATP pocket of HSP90α and HSP90β with Ka of 30 nM and 30 nM, uniformly more potent than 17-AAG. (11) (1)
S1290 Celastrol (NSC 70931) Celastrol (NSC 70931, Tripterine) is a potent proteasome inhibitor for the chymotrypsin-like activity of a purified 20S proteasome with IC50 of 2.5 μM. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway. Celastrol inhibits dopaminergic neuronal death of Parkinson's disease through activating mitophagy. (8) (2)
S1141 Tanespimycin (17-AAG) Tanespimycin (17-AAG, CP127374, NSC-330507, KOS 953) is a potent HSP90 inhibitor with IC50 of 5 nM in a cell-free assay, having a 100-fold higher binding affinity for HSP90 derived from tumour cells than HSP90 from normal cells. Tanespimycin (17-AAG) induces apoptosis, necrosis, autophagy and mitophagy. Phase 3. (96) (9)

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