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TH-302 is a highly potent and selective hypoxia-activated pro-drug targeting hypoxic regions of solid tumors with an IC₅₀ of 19 nM. It is stable to liver microsomes. However, under hypoxic conditions, it is selectively and irreversibly converted to its active phosphoramidate-based, DNA-crosslinking, bis-alkylator. TH-302 inhibits H460 cells and HT29 cells with IC₉₀ of 0.1 μM and 0.2 μM, respectively. It shows much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. TH-302 exhibits potent cytotoxicity to both human and murine MM cells with hypoxic selectivity and dose dependency, and induces G0/G1 cell-cycle arrest under hypoxic conditions. It inhibits primary tumor growth in multiple xenograft models. TH-302 is currently in a phase II clinical trial for the treatment of soft tissue sarcoma.

How to Use:

• In vitro: TH-302 was used at 1 μM concentration in vitro and cellular assays.
• In vivo: TH-302 was intraperitoneally (IP) dosed to mice at 50 mg/kg once per day to inhibit tumor growth.

Reference:

1. 1. Duan JX, et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. (2008) J Med Chem. 51(8):2412-20.
2. 2. Hu J, et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. (2010) Blood. 116(9):1524-7.
3. 3. Weiss GJ, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies. (2011) Clin Cancer Res. 17(9):2997-3004.
4. 4. Meng F, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. (2012) Mol Cancer Ther. 11(3):740-51.
5. 5. Sun JD, et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. (2012) Clin Cancer Res. 18(3):758-70.
6. 6. Moyer MW. Targeting hypoxia brings breath of fresh air to cancer therapy. (2012) Nat Med. 18(5):636-7.

Products are for research use only. Not for human use.