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Description
Oncothyreon's lead compound targeting HIF-1α is PX-478, a novel small molecule inhibitor of HIF-1α protein. PX-478 is effective when delivered orally in animal models, and was shown to produce marked tumor regression and growth inhibition in such model systems of cancers including lung, ovarian, renal, prostate, colon, pancreatic, breast and glioma. Additional preclinical studies have demonstrated that PX-478 enhances the therapeutic effects of radiation therapy. These data suggest that PX-478 may have clinical utility either as a single agent or in combination with radiation therapy.
Mechanistic studies have shown that PX-478 decreases both HIF-1α gene expression and protein synthesis, resulting in a significant reduction of HIF-1α in tumor tissue. PX-478 is highly specific for HIF-1α and this inhibitory effect is independent of the tumor suppressor genes VHL and p53.
PX-478: Targeting H1F-1α
HIF-1α
- Expressed at relatively low levels in normal tissue
- Cellular protein induced in response to lower oxygen levels
- Overexpressed in a wide range of primary tumors
- Key factor in the cascade of events leading to angiogenesis
- High levels found in tumors that lack VHL protein (renal)
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