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ONCOGENES AND HSP90 INHIBITORS

PATHWAY OF HSP90 AND CANCER CELL LINES:
Heat shock protein 90 or Hsp90 is actually a non-fibrous protein which gained its name from its molecular weight that is 90kDa. Hsp90 is most abundant cytoplasmic protein which plays a significant role in cells by acting like a molecular chaperone for many proteins related to some important signaling cascades of the cell. Different proteins chaperones that are existing in the cell, involve serine/theronine kinases and tyrosine kinases as well hence they are very much important for the proper regulation of cell growth and cell cycle. A detailed research is carried out to describe the relation between Hsp90 and cancers [1]. To inhibit this chaperone i.e. Hsp90, the simple strategy of designing Hsp protein inhibitor was developed when Hsp90 was found to be existing in different cancerous cell lines activated through the activation of oncogenes [2]. It has been proved a very fruitful therapy for cancer.


DESIGNING HSP90 INHIBITORS AND THEIR PHARMACOLOGY:
Different agonists and antagonists of hsp90 are used by various research groups to evaluate the complexity of regulation of hsp90 in neoplastic and normal cells that may be helpful in the production of some potent and novel Hsp90 inhibitors [3]. These drugs are not costly and are in easy access of researcher as they can buy them from respective supplier. Many of these inhibitors are characterized by using the compound library screening. Characterization of Cancerous cells is carried out by various hyperactive pathways like AKT, EGFR, PI3K etc., so the use of specific inhibitors of the pathways of Hsp90 can stop the function of this pathway ultimately triggering the apoptosis. A famous example of these inhibiting molecules is Geldanamycin and also its analog 17-allylaminogeldanamycin or 17-AAD, SNX-2112, PU-H71, PU24FC1, Celastrol and Rifabutin ect. Among these inhibitors majority is specific for the Hsp90 while a few can inhibit more than one molecule.


HSP90 INHIBITORS: CLINICAL EVALUATION
Various actions and effects of Hsp inhibitors on Hsp90 are being noted when they were evaluated in different testing trials hence leading to the discovery of best and efficient inhibitors for the therapy of cancers. NCI or National Cancer Institute has conducted a clinical testing of SNX-5422 in which lymphomas and solid tumors (NCT00644072) were put under in vitro treatment and gave remarkable results. Animal models exhibiting cancer were directed with this inhibiting drug and as a result an inhibition of AKT and ERK pathways to reduce the growth and proliferation of tumor and angiogenesis of tumor cells was reported [4]. Geldamycin is a chemical antibiotic derived from the benzoquinone is the most familiar Hsp90 inhibitor and was found in bacterial strain Streptomyces hygroscopicus [5]. It was also reported that it causes a cell cycle arrest in a way independent of MAP kinase [6]. 17-N-Allylamino-17-demethoxygeldanamycin or 17-AAG that is a Geldamycin derivative molecule was used for the treatment of renal cancer, leukemia and solid tumors and showed very good results. Another molecule named Celastrol has gained appreciation in clinical studies due to its irreversible targeting the Go/G1 stage of cell cycle in cells of monocytic human leukemia [7]. Similarly a lot of other inhibitors are still under the pre-clinical stages and will surely be called for the clinical assessment after showing some 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
S2713 Geldanamycin Geldanamycin is a natural existing HSP90 inhibitor with Kd of 1.2 μM, specifically disrupts glucocorticoid receptor (GR)/HSP association. (9) (3)
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. (6) (1)
S2656 PF-04929113 (SNX-5422) PF-04929113 (SNX-5422) is a potent and selective HSP90 inhibitor with Kd of 41 nM and induces Her-2 degradation with IC50 of 37 nM. Phase 1/2. (3) (3)
S1141 Tanespimycin (17-AAG) Tanespimycin (17-AAG) 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. Phase 2. (33) (9)

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