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Small Molecule Inhibitors of Thioredoxin Reductase as Cancer Therapeutics

详细技术说明

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*Abstract

Investigators have developed PX-916, a water soluble prodrug of Palmarumycin CP1, a natural product inhibitor of Thioredoxin reductase. In its natural form, the utility of Palmarumycin CP1 is limited by its water solubility, which therefore impacts its bioavailability. PX-916 is converted to active drug at physiological pH but is stable at acid pH. PX-916 demonstrates excellent antitumor activity both in vitro and in vivo in multiple human tumor xenograft models. Applications1) Novel anti-cancer agent against multiple tumor types2) May have activity in other diseases where thioredoxin reductase is thought to play a pathophysiologic role such as: a) Diabetic neuropathy b) Rheumatoid arthritis c) SjogrenΓÇÖs syndrome d) AIDS e) Reperfusion injuryAdvantages1) Analogs may be used to create lead compounds with greater efficacy and potency2) Pro drugs can also be developed which cleave into an active compound under physiological conditions3) Water soluble prodrug is stable at acid pH which allows iv administration then releases the parent drug at physiological pH and in plasma4) Active against multiple human tumor types o Breast Cancer o Rhabdomyosarcoma o Small Cell Lung CancerStage of Development* Activity in three human tumor xenograft mouse models* Preclinical pharmacokinetics, toxicity and stability of lead compound have been defined European Patent Application EP1933820Canadian Patent Application CA2622674

*Principal Investigation

Name: Garth Powis

Department: Department of Experimental Therapeutics -- Unit 422

Name: Peter Wipf, Professor

Department: Chemistry

国家/地区

美国