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Small Molecule-Mediated Anti-Cancer Therapy via Hypoxia Inducible Factor-1 Blockade

Despite reservations regarding potential toxicities, small molecule- mediated blockade ofthe hypoxia- inducible factor- 1 transcription factor has emerged as a viable anti-cancerstrategy in vivo. Recent experiments by Welsh et al. 1 revealed unprecedented anti- tumorresponses of various aggressive solid tumors to the HIF-1- inhibitory small molecule drugPX-478. Compared with other anti- cancer drugs, PX-478 had markedly improvedregression, growth delay and log10 cell kill profiles, particularly against large tumors thatare normally refractory to small molecule drug therapy. Importantly, pharmacokineticand toxicity profiles were within acceptable limits, providing rationale for the clinicaldevelopment of HIF-1 inhibitors in general. Though the mechanism of action for PX-478is not completely understood, inhibition of glycolysis rather than angiogenesis appearedto be the primary mode of anti- cancer activity.