{"id":504,"date":"2016-08-18T22:17:51","date_gmt":"2016-08-19T03:17:51","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=504"},"modified":"2016-08-18T22:17:51","modified_gmt":"2016-08-19T03:17:51","slug":"recent-updates-on-the-development-of-ganetespib-as-a-hsp90-inhibitor","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/recent-updates-on-the-development-of-ganetespib-as-a-hsp90-inhibitor\/","title":{"rendered":"Recent Updates on the Development of Ganetespib as a Hsp90 Inhibitor"},"content":{"rendered":"

Heat shock protein 90<\/a> (Hsp90) is a highly conserved\u00a0molecular chaperone which modulates cellular homeostasis and environmental stress responses by interacting with more than 200 proteins, also known as Hsp90\u00a0client proteins, to facilitate their folding and maturation processes. Hsp90 comprises an N-terminal ATP-binding domain,\u00a0a central domain that regulates the ATPase activity of\u00a0the N-terminal domain, and a C-terminal domain that\u00a0mediates constitutive Hsp90.<\/p>\n

It was reported that Hsp90 can help tumor cells to\u00a0maintain the malignant state with assistance of many\u00a0oncoproteins, including Bcr-Abl, B-Raf, HIF-1\u03b1, mutated\u00a0EGFR, HER2\/neu, mutant p53, and many others, in a\u00a0similar manner to normal cells. Accordingly, Hsp90 was\u00a0suggested as a novel target for cancer therapy. Furthermore, the results of a study revealed that its inhibitors\u00a0have the potential to target multiple cancer processes\u00a0such as evading apoptosis, insensitivity to anti-growth\u00a0signals, sustained angiogenesis, tissue invasion and\u00a0metastasis, limitless replicative potential and self-sufficiency in growth signals.<\/p>\n

A variety of Hsp90 inhibitors have been tested in preclinical and clinical trials. The first-generation of Hsp90\u00a0inhibitors are benzoquinone ansamycins, including geldanamycin<\/a> and its derivatives tanespimycin<\/a> (17-AAG)\u00a0and alvespimycin<\/a> (17-DMAG). However, the clinical progression of this group has been hampered because of several drawbacks including poor solubility,\u00a0formulation problems, potential multidrug efflux, and\u00a0hepatotoxicity. Also, as monotherapy, these inhibitors have only\u00a0shown modest efficacies in the clinical setting, indicating that they\u00a0may be useful only in combination therapies along with\u00a0other cancer drugs. In an effort to overcome these limitations, several second-generation Hsp90 inhibitors featuring different chemotypes and potencies are currently under development. Among which, ganetespib<\/a>\u00a0and NVP-AUY992 are involved in most active clinical\u00a0trials. The clinical trials of NVP-AUY922 are focused\u00a0on combination therapy, whereas the focus for ganetespib lies on\u00a0monotherapy as well as combination therapy of a variety of adaptations.<\/p>\n

Ganetespib (3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole, STA-9090), a novel resorcinol-containing triazole compound\u00a0unrelated to the ansamycin family of Hsp90 inhibitors, is one of the\u00a0most promising Hsp90 inhibitor. It was reported that\u00a0ganetespib displayed superior potency to the firstgeneration inhibitors and is currently in a phase III\u00a0clinical trial led by Synta Pharmaceuticals. Herein, the current status\u00a0and updates on the development of ganetespib will be\u00a0described based on recent reports.<\/p>\n

According to the patent for triazole-based Hsp90\u00a0inhibitors by Synta pharmaceuticals, it was suggested\u00a0that ganetespib binds to the ATP-binding pocket at\u00a0the N-terminus of Hsp90. Inhibition of Hsp90, in general, is thought to cause aberrant\u00a0conformations of Hsp90 client proteins, which triggers\u00a0ubiquitination-dependent degradation of client proteins\u00a0via proteasomes.\u00a0Ganetespib exhibits potent in vitro <\/em>cytotoxicity in a range of\u00a0solid and hematologic tumor cell lines, including those\u00a0that express mutated kinases that confer resistance to\u00a0small-molecule tyrosine kinase inhibitors. Ganetespib\u00a0treatment rapidly induced the degradation of known\u00a0Hsp90 client proteins, displayed superior potency to\u00a0tanespimycin, and exhibited sustained activity even\u00a0with short exposure times. In vivo<\/em>, ganetespib showed\u00a0potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by\u00a0significant growth inhibition and\/or regression. In particular, evaluation of the microregional activity of\u00a0ganetespib in tumor xenografts showed that this compound was efficiently distributed throughout the\u00a0tumor tissue, including the hypoxic regions >150 mm\u00a0from the microvasculature, to inhibit proliferation and\u00a0induce apoptosis. Importantly, ganetespib showed no\u00a0evidence of cardiac or liver toxicity.<\/p>\n

Altogether, inhibitors of Hsp90 are proven to achieve\u00a0their promising anticancer activities through degradation of multiple oncoproteins within cancer cells. Gane\u00a0tespib exhibited increased potency and better safety\u00a0profiles in preclinical models over tanespimycin and\u00a0has, so far, been safe in phase I clinical trials involving\u00a0patients with solid tumors. Several phase II clinical\u00a0trials are underway and a phase III clinical trial commenced at the time of publication. This preclinical activity profile showing select mechanistic and safety\u00a0advantages over other first- or second-generation Hsp90\u00a0inhibitors indicates that ganetespib may have broad\u00a0applications for a variety of human malignancies. The\u00a0information from preclinical and clinical trials of ganetespib will be useful for development of cancer therapy\u00a0with Hsp90 inhibitors and give positive impacts to\u00a0subsequent applications of Hsp90 inhibitors.<\/p>\n

\u00a0<\/strong><\/p>\n

Reference:<\/strong><\/p>\n

Hyun Kyung Choi<\/strong>\u00a0<\/strong>and Kyeong Lee<\/strong>. <\/strong>Arch Pharm Res Vol 35, No 11, 1855-1859, 2012<\/em><\/p>\n

Related Products:<\/p>\n

<\/div>
<\/th><\/th><\/th><\/th><\/th><\/tr><\/thead>
CAS Number <\/td>Product Name <\/td>Molecular Formula <\/td>Molecular Weight <\/td>Description <\/td><\/tr>
888216-25-9 <\/td>Ganetespib<\/a><\/td>C20H20N4O3 <\/td>364.40 <\/td>Ganetespib, also known as STA-9090, is a synthetic small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. <\/td><\/tr>
467214-20-6 <\/td>Alvespimycin<\/a><\/td>C32H48N4O8 <\/td>616.75 <\/td>Alvespimycin (17-DMAG; KOS-1022; NSC 707545) is a potent, H2O-soluble Hsp90 inhibitor with IC50 of 62 nM.17-DMAG displays ~2 times potency against human Hsp90 than 17-AAG, with IC50 of 62 nM versus 119 nM. <\/td><\/tr>
75747-14-7 <\/td>Tanespimycin<\/a><\/td>C31H43N3O8 <\/td>585.69 <\/td>17-AAG is an orally bioavailable, small-molecule inhibitor of several receptor protein tyrosine kinases with potential antiangiogenic and antineoplastic activitie, binds to and inhibits the vascular endothelial growth factor receptors (VEGFRs) type 2 and 3, platelet-derived growth factor receptor beta (PDGFRb) and c-Kit, which may result in the inhibition of angiogenesis and cellular proliferation in tumors in which these receptors are upregulated. <\/td><\/tr>
30562-34-6 <\/td>Geldanamycin<\/a><\/td>C29H40N2O9 <\/td>560.64 <\/td>Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and inhibits its function. Hsp90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. <\/td><\/tr><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"

Heat shock protein 90 (Hsp90) is a highly conserved\u00a0molecular chaperone which modulates cellular homeostasis and environmental stress responses by interacting with more than 200 proteins, also known as Hsp90\u00a0client proteins, […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[292,290,291],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/504"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=504"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/504\/revisions"}],"predecessor-version":[{"id":505,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/504\/revisions\/505"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=504"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=504"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=504"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}