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