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Table 2 HIF-1α inhibitors and proposed mechanisms of action

From: Gene expression and hypoxia in breast cancer

Name Class of drug Mechanism of action Current status as a cancer therapy
Digoxin Cardiac glycoside Inhibits HIF-1-dependent gene transcription but precise mechanism unclear Under evaluation in early phase trials in lung and prostate cancer www.clinicaltrials.gov
AFP464 Aminoflavine prodrug (DNA-damaging agent) Inhibition of HIF-1α mRNA expression but precise mechanism unclear Early evidence of clinical activity in heavily pre-treated advanced solid tumors in phase 1 trials [98]
Topotecan and EZN-2208 Topoisomerase-1 inhibitors and cytotoxic agents Inhibition of HIF-1α-mediated protein translation by a Top1-dependent but DNA damage-independent mechanism Topotecan licensed for treatment of advanced lung, cervical and ovarian cancer.
EZN-2208 undergoing evaluation in phase 2 trials for treatment of metastatic breast and colorectal cancer www.clinicaltrials.gov
Doxorubicin and daunorubicin Anthracyclines Inhibits binding of HIF-1α to the HRE sequence Anthracyclines licensed to treat breast, bladder and lung cancer, several hematological malignancies and sarcoma
Echinomycin Quinoxaline antibiotic Inhibits HIF-1 binding to DNA Minimal evidence of efficacy in the treatment of solid tumors in phase 2 trials [99]
Everolimus mTOR inhibitor Inhibits HIF-1α target protein translation Licensed for treatment of advanced renal cancer
Bortezomib Proteasome inhibitor Repression of HIF-1α transcriptional activity by inhibiting recruitment of the p300 co-activator by FIH Licensed for treatment of multiple myeloma. Under evaluation in early-phase trials in solid tumors
Geldanamycin or tanespimycin HSP-90 inhibitor Failure to recruit HIF-1α cofactors for downstream protein transcription Early evidence of clinical activity in advanced solid and hematological malignancies in early phase trials [100, 101]
PX-478 Melphalan derivative Inhibits HIF-1α protein levels and HIF-1 transcriptional activity in a p53- and pVHL- independent manner Early evidence of clinical activity in advanced solid tumors in a phase 1 trial [102]
Compound DJ12   Downregulates the mRNA of downstream targets of HIF-α, inhibits HIF-1α transactivation activity by blocking HIF-1α HRE-DNA binding Preclinical
YC-1 Synthetic benzylindazole derivative FIH-dependent inactivation of the CAD of HIF-1α Pre-clinical