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HSP90 INHIBITORS AND ONCOGENES

HSP90 PATHWAY AND CANCER CELLS:
Heat shock protein 90 or Hsp90 is a non-fibrous protein that has gained its name from its 90kDa molecular weight. This is the most abundant protein present in cytoplasm and plays an important role in the cell by acting as a chaperone for many of the proteins involved in important signaling pathways of the cell. There are various proteins chaperones which are present in the cell, includes TKs or tyrosine kinases and theronine/serine kinases as well and these are very important for the regulation of cell cycle and growth. Detailed research has been conducted to connect cancers and Hsp90 [1]. As Hsp90 has shown by different cancerous cells which are activated via activating oncogenes [2] a simple strategy for the inhibition of this chaperone has developed by designing Hsp90 inhibitors. This approach has been fruitful for cancer therapy.


DEVELOPMENT OF HSP90 INHIBITORS AND PHARMACOLOGY:
Various hsp90 agonists and hsp90 antagonists are used by research groups in order to identify the complexity of hsp90 regulation in normal and neoplastic cells which may help in the development of potent novel Hsp90 inhibitors [3]. These molecules are not very costly and have easy access for researcher as one can buy them from any of the supplier. By the help of compound libraries for drug discovery many of these are characterized. Cancer cells are characterized by different hyperactive pathways such as PI3K, AKT, EGFR etc., hence the usage of specific pathway inhibitors of Hdp90 can check the activity of this pathway and ultimately apoptosis will be triggered. One of the famous example of these inhibitors is Geldamycin and its analog 17-AAD or 17-allylaminogeldanamycin, PU-H71,SNX-2112,PU24FC1,Rifabutin and Celastrol ect. Majority of these inhibitors are specific for Hsp90 where as a few can inhibit over one molecule.


CLINICAL EVALUATION OF HSP90 INHIBITORS:
A good number of Hsp inhibitors are being evaluated in the clinical testing trials where their actions are noted on Hsp90 which can ultimately lead to the best effective inhibitors for cancer therapy. National Cancer Institute or NCI conducted a clinical trial of SNX-5422 where solid tumors (NCT00644072) and lymphomas were treated under in vitro conditions and it generated efficient results. In models of animals having cancers were administered with this drug and it was reported that it inhibited the ERK and AKT pathways in order to reduce tumor growth proliferation and angiogenesis of cancer cells [4]. The most famous Hsp90 inhibitor Geldamycin is chemical an antibiotic and derived from benzoquinone that was found in Streptomyces hygroscopicus [5]. It is also reported to arrest cell cycle in a MAP kinase independent manner [6]. Geldamycin derivative 17AAG or 17-N-Allylamino-17-demethoxygeldanamycin is used for the therapy of leukemia, kidney and solid tumors where it showed efficient results. Celastrol is another molecule that has gained recognition in clinical trials as it targets cell cycle at Go/G1 stage in a reversible manner of monocytic human leukemia cells [7]. And similarly many other inhibitors are under preclinical stages which will be called for clinical assessment 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. (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)
S2713 Geldanamycin Geldanamycin is a natural existing HSP90 inhibitor with Kd of 1.2 μM, specifically disrupts glucocorticoid receptor (GR)/HSP association. (9) (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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