Table 1.
Potential HIF-1 inhibitors under development.
| HIF-1 Inhibitors | Target Molecules | Tumors/Cell Lines |
|---|---|---|
| Transcriptional initiation | ||
| Flavopiridol | blocking phosphorylation of RNA polymerase II’s COOH-terminal domain | acute myeloid leukemia, advanced renal cell carcinoma |
| Aminoflavone | AhR | breast cancer cells (MCF7), human renal cell lines |
| mRNA stabilization | ||
| EZN-2968 | HIF-1α mRNA | prostate (15PC3, PC3, and DU145), glioblastoma (U373) cells, duodenal neuroendocrine tumor |
| Translational initiation | ||
| Rapamycin | mTOR | prostate cancer cells (PC-3) |
| Cetuximab | EGFR | HNSCC cells (FaDu, HN5, UMSCC1, and OSC19) |
| Buparlisib | PI3K | breast cancer |
| KC7F2 | mTOR, S6K, 4EBP1 | U251MG, MCF7, PC3, LNZ308, LN229 cells |
| 2-MEs | tubulin | MCF7, MDA-MB-231, PC-3, ovarian cancer, multiple myeloma |
| Digoxin | Na+/K+ ATPase | Hep3B, 293, 293T, PC3, P493 |
| AZD6738, VX-970 | ATR | esophageal cancer cells (OE21, FLO-1) (VX-970) |
| Protein stabilization | ||
| Melatonin, NB-5-MT | GSK-3β, activating PHDs | colon cancer cells (HCT116), prostate cancer cells (DU145, PC-3, LNCaP), breast cancer cells (MCF-7, MDA-MB-231), renal cell carcinoma (RenCa) |
| LW6 | inducing pVHL expression | HCT116 |
| GYY4137 | slow-releasing H2S donor | HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11, U2OS |
| Ganetespib | ATP-binding site of HSP90 | NSCLC (NCI-H1975, HCC827) cells, colorectal cancer (HCT116, HT29), non-small cell lung cancer |
| Apigenin | CK2 activity | multiple myeloma cells, pancreatic cancer cells (S2-013, CD18) |
| Lonafarnib | interaction between HSP90 and HIF-1α | non-small cell lung carcinoma, breast cancer |
| Vorinostat | increasing acetylation of HSP90 | Hep3B, HepG2, U2OS, MG63, U87 MG, HuH7 |
| Romidepsin (FK228) | HDAC | Lewis lung carcinoma (LLC), HT1080 |
| Trichostatin | HDAC | tongue squamous cell carcinoma SCC-6, BAECs, 786-0 (VHL-negative), HEK 293 cells, Lewis lung carcinoma cells, HepG2 |
| Heterodimerization | ||
| Acriflavine | PAS-B domain of HIF-1α | HEK293, HeLa, Hep3B-c1, PC-3, P493 |
| DNA binding | ||
| Echinomycin | binding to HRE sequences | U251, MCF-7, non-small cell lung carcinoma, soft tissue sarcoma |
| Anthracycline | HIF-HRE binding | HK-2. HeLa, A498, KMRC-3 VHL-defective renal cell carcinoma (RCC) cells, Caki-1 VHL-competent renal cell carcinoma cells |
| Radicicol | HIF-DNA binding, HSP90 | SKBR3, Hep 3B |
| Transactivation | ||
| Bortezomib | PI3K/Akt/mTOR, MAPK, p300 recruitment | prostate cancer cells, Hep3B, HEK293, ARH77, U299 cells, RCC, breast cancer, rectal carcinoma, nasopharyngeal, neuroendocrine carcinoma, prostate cancer |
| Other steps | ||
| PX-478 | inhibiting HIF-1α deubiquitination, reducing HIF-1α mRNA and HIF-1α translation | PC-3, MCF-7, HT-29, Panc-1, BxPC-3 cells, RCC4, RCC4/VHL, HCT116 |
| Camptothecin analogues (TPT, EZN-2208) | topoisomerase-1 | HEK293, U251, leukemia cell lines, neuroblastoma cells (GI-LI-N, LAN-5) derived from metastatic |
| CRLX101 | topoisomerase-1 | ovarian cancer, breast cancer, renal cell carcinoma |
| Metformin | Mitochondria complex I, XBP1 | HCT116, HCC, NSCLC, etc. |
AF, aminoflavone; AhR, aryl hydrocarbon receptor; ATR, ataxia telangiectasia and Rad3-related kinase; CK2, casein kinase 2; EGFR, epidermal growth factor receptor; HDACs, histone deacetylases; HIF-1, hypoxia-inducible factor 1; HNSCC, head and neck squamous cell carcinoma; HRE, hypoxia response element; H2S, hydrogen sulfide; HSP90, heat shock protein 90; GSK-3β, glycogen synthase kinase-3β; MAPK, mitogen-activated protein kinase; 2-ME, 2-methoxyestradiol; RCC, renal cell carcinoma; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; PAS, Per-Arnt-Sim; PI3K, phosphatidylinositol-3-kinase; pVHL, von Hippel-Lindau protein; TPT, topotecan; TSA, trichostatin A; XBP1, X-box binding protein 1.