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HSP990

HSP990 is an oral inhibitor of HSP90 being developed by Novartis.

The following trial of this new drug is planned to open soon:

A Study of HSP990 Administered by Mouth in Adult Patients With Advanced Solid Tumors

This trial is not yet open for recruitment. It will be a multi-center Phase I clinical trial to study the safety, tolerability and metabolism of a drug called HSP990 which is a heat shock protein 90 inhibitor (Hsp). The treatment is open label, and will be given to subjects with advanced solid tumors, anticipated to start in 2009. Each treatment cycle consists of the patient taking HSP990 orally once a week for four weeks. The study’s initial goal is to establish the maximum tolerated dose, with further goals of establishing the true DLT rate, the drug’s efficacy against the tumor, and to study its metabolism. The Primary Completion Date is November 2010. Novartis is the drug’s manufacturer and the trial sponsor. It is hoped to recruit 60 subjects to the trial, who must be over 17, and who must have had progression on standard therapy or for whom no standard therapy exists, and an existing lesion. However, patients must not have previously taken any Hsp, or HDAC inhibitor compounds. Patients will also be need to be more than two weeks post surgery, and time must have elapsed since treatment with other therapies. The other excluded group of patients are those who are identified to be "poor CYP2C9 metabolizers".

The following information was provided by Novartis in June 2009:

Blocking tumor growth by inhibiting heat shock protein 90 (HSP90)

Heat shock proteins (HSP) are molecular chaperones that assist in the structural formation and folding of a wide variety of oncogenic client proteins such as HER2, ER, c-Met, N-RAS, AKT, C-KIT, PDGFR, VEGFR, and B-RAF. The mutated forms of such proteins are generally more dependent on the chaperoning function of HSP90. If these proteins are misfolded, they become subject to ubiquitination and proteosomal degradation. HSP90 is the most abundant molecular chaperone and is essential for cell survival, proliferation, and apoptosis.

HSP90 is an important target for cancer chemotherapeutics because tumor cells, especially those with mutations, exist in a stressful environment and depend on HSP90 to grow and survive. If HSP90 is inhibited, the regulation of tumor cell survival, proliferation, and apoptosis are significantly affected. For this reason, HSP90 inhibitors are considered to be agents with strong therapeutic potential in a wide variety of tumor types. In tumors, HSP90 exists in an activated state (complex), with higher affinity for HSP90 inhibitors, compared with normal cells, which provides opportunity for a therapeutic window.

Hsp90 inhibitors have been shown to be synergistic with a range of standard therapeutic agents and to sensitize tumor cells to cytotoxic effects of these agents. Hsp90 inhibitors such as HSP990 could thus be effective in combination therapy.

Novartis Oncology is currently developing two novel, highly potent, non-geldanamycin derivative HSP90 inhibitors that competitively inhibits the ATPase activity of HSP90, AUY922 (i.v.) and HSP990 (oral). Both in vitro and in vivo studies indicate that AUY922 and HSP990 have significant antitumor activity in a wide range of mutated and wild-type cancer cell lines, primary tumor cells, and animal models of cancer, including breast cancer, multiple myeloma, gastric cancer, NSCL cancer, different types of sarcomas and others.

HSP990 is an orally bioavailability synthetic small molecule, which potently and selectively inhibits Hsp90 via binding to the ATP binding site. The proliferation of multiple human tumor cell lines is inhibited in a dose-dependent manner with GI50 values in the low nM range. After oral administration to mouse, rat or dog, HSP990 is well absorbed and has 40-100% bioavailability with low to moderate clearance, large volume of distribution and long half-life. Currently, HSP990 is being investigated in Phase I/ Dose escalation clinical trial in patients with advanced solid tumor malignancies. A second joined Dose-escalation study in Japan-Korea is planned to start Dec2009/Jan 2010.



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