Hsp90 inhibitor

An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG). An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG). Among heat shock proteins the focus on HSP90 has increased due to its involvement in several cellular phenomena and more importantly in disease progression. HSP90 keeps the death proteins in an apoptosis resistant state by direct association. Its wide range of functions results from the ability of HSP90 to chaperone several client proteins that play a central pathogenic role in human diseases including cancer, neurodegenerative diseases and viral infection. Geldanamycin directly binds to the ATP-binding pocket in the N-terminal domain of Hsp90 and, hence, blocks the binding of nucleotides to Hsp90. Analysis of the effects of Geldanamycin on steroid receptor activation indicates that the antibiotic blocks the chaperone cycle at the intermediate complex, preventing the release of the receptor from Hsp90 and, eventually, resulting in its degradation. Ewing’s sarcoma shows several deregulated autocrine loops mediating cell survival and proliferation. So their blockade is a promising therapeutic approach. Proteosome analysis revealed that Hsp90 is differentially expressed between ewing’s sarcoma cell lines, sensitive and resistant to specific IGF1R/KIT inhibitors. The in vitro IGF1R/KIT pathway blockade on ewing’s sarcoma cell lines and classified ewing’s sarcoma cell lines as resistant and sensitive to blockade of pathway. Inhibition of Hsp90 with 17AAG and siRNA resulted in reduction of cell lines growth and survival. The inhibition of Hsp90 causes the proteosomal destruction of client proteins- Akt, KIT and IGF1R. This effect could be due to precluding physical contact between client proteins and Hsp90. So since the molecular chaperones are overexpressed in a wide variety of cancer cells and in virally transformed cells, inhibiting the function of these chaperones is essential to controlling cancer cells, as this would affect the activity of signaling proteins. The availability of drugs that can specifically target Hsp90 and inhibit its function, resulting in the depletion of client proteins, has made Hsp90 a novel and exciting target for cancer therapy. The current HSP90 inhibitors are developed from geldanamycin and radicicol which are the natural product inhibitors and are starting point for new approach. HSP 90 is required for ATP dependent refolding of denatured or unfolded proteins and for the conformational maturation of a subset of proteins involved in the response of cells to extracellular signals. These include steroid receptors Raf – 1, Akt, Met and Her 2. HSP90 has conserved unique pocket in N terminal region. It binds ATP & ADP and has weak ATPase activity. This suggests that site acts as nucleotide or nucleotide ratio sensor. It is observed that nucleotides adopt unique C shaped bent shape when binding to this pocket. This is particularly unusual as nucleotides never adopt shape change in high affinity ATP/ADP sites. This also indicates that drugs that are developed should also have potential to adopt unique C shape conformation in order to bind the unique pocket. The rationale for this unusual need i.e. to bend the structure, is based on thermo dynamical fact that the molecule which needs minimum structural changes to go from unbound to bound state should not pay much entropic penalties and binding would be reflected by enthalpic factors. Geldanamycin and radicicol tightly bind to this pocket and prevent the release of protein from chaperone complex. Thus the protein cannot achieve native conformation and is degraded by proteosome. Addition of such inhibitor causes proteosomal degradation of signaling proteins like steroid receptors, Raf kinase and Akt. Geldanamycin and radicicol also inhibit mutated protein in cancer cells like P53, Vsrc, BCR – ABL. It is worth to note that the normal counterparts are not inhibited. Geldanamycin is an effective HSP90 inhibitor still it cannot be used in vivo because of its high toxicity and liver damage ability. The speculation is that the benzoquinone functional group is responsible. The semi-synthetic derivative 17 AAG, with lower toxicity but same potency as geldanamycin is developed and is currently under clinical trials. 17-N-Allylamino-17-demethoxygeldanamycin (17AAG) is the semi-synthetic derivative of natural product Geldanamycin. It is less toxic with same therapeutic potential as Geldanamycin. It is the first HSP90 inhibitor to be evaluated in clinical trials. Currently 17AAG is being evaluated as potent drug against AML. It is known that 17 AAG decreases the concentration of client proteins but it was a question of debate if 17 AAG affected the genes for client proteins or it inhibited cytosolic proteins. Gene expression profiling of human colon cancer cell lines with 17AAG proves that Hsp90 client protein genes are not affected but the client proteins like hsc, keratin 8, keratin 18, akt, c-raf1 and caveolin-1 are deregulated resulting in inhibition of signal transduction. Acute myelogenous leukemia (AML) remains the most common form of leukemia in the adult and elderly population. Currently, anthracyclines, cytarabine and etoposide are widely used in the treatment of AML due to their ability to induce apoptosis in leukemic cells. The signaling pathways by which these drugs work are not completely understood, but direct effects as DNA damage, mitochondrial electron transport interference, generation of oxidizing radicals and proteasomal activation have been demonstrated or hypothesized. The 17-allylamino-17-demethoxygeldanamycin (17-AAG) derivative of GA is currently in clinical trial in cancer. Under normal conditions, Hsp90 acts on a wide range of client proteins and is essential for conformational maturation of numerous oncogenic signaling proteins, including protein kinases and ligand-regulated transcription factors. Hsp90 acts in a multiprotein complex with several co-chaperones. One of these, cochaperone p23, appears to stabilize Hsp90-complexes with steroid receptors and oncogenic tyrosine kinases. p23 also has chaperone activity on its own and is able to inhibit aggregation of denatured proteins in the absence of ATP. The ATP antagonist GA and its derivative 17AAG blocks p23 association with Hsp90, induces proteasomal degradation of survival signaling. Hsp90 client proteins, activates the apoptosis-associated doublestranded RNA-dependent protein kinase, PKR and promotes an apoptotic rather than a necrotic death type. p23 has increased expression in mammary carcinomas. In their study, Gausdal and colleagues found that anthracyclines and other chemotherapeutic drugs like cytarabine and etoposide, but not GA alone, induced caspase-dependent cleavage of p23. The cleavage could be catalyzed by either caspase-7 or caspase-3 and occurred at D142 or D145 in the C-terminal tail of p23 that is believed to be required for chaperone activity. The Hsp90 inhibitor GA was found to enhance caspase activation, p23 cleavage and apoptosis induced by anthracyclines. Finally they concluded that Hsp90, and consequently signaling mediated by client proteins in the Hsp90 multiprotein complex, may be targeted through p23 in chemotherapy-induced cell death in AML.