A HYPOXIA ACTIVATED HIF-1 & INHIBITOR FOR CANCER THERAPY

DESCRIPTION (provided by applicant): ProlX Pharmaceuticals, a company focusing on redox targets for development of anti-cancer therapies, has identified PX-478 as a novel hypoxia inducible factor (HIF) inhibitor and hypoxic bystander anti-cancer agent. The initial Phase I SBIR proposal, with aims to synthesize and evaluate novel agents that would be activated within a hypoxic tumor environment, provided strong evidence that PX-478 is selectively activated by hypoxic cancer cells and is an inhibitor of increased HIF-1 alpha and vascular endothelial growth factor (VEGF) production by the cells. The objective of this Phase II SBIR proposal is to move PX-478 through more extensive pre-clinical development. The specific aims of the proposal are: 1) to synthesize three salt preparations of PX-478 and to evaluate the physical chemical properties and properties and pharmacokinetics of each preparation to select a candidate for formulation and bioavailability studies; 2) to expand animal model evaluation of PX-478 and develop a biological endpoint assay based upon inhibition of HIF/VEGF expression; 3) to perform GLP toxicological evaluation of PX-478 in rodent and dog species. The conclusion of this Phase II SBIR will see ProIX Pharmaceuticals move PX-478 through complete pre-clinical development to IND submission to the FDA. PROPOSED COMMERCIAL APPLICATION: One in every five deaths in the US is doe to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is a significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake full preclinical development of a novel anti HIF/hypoxic bystander, PX-478, and initiate a Phase I clinical trial for its eventual use as a therapy against cancer.