TH-302

TH-302 is a hypoxia-activated prodrug and DNA alkylating agent with anticancer activity.¹ It is selectively cytotoxic to H460 human non-small cell lung cancer (NSCLC) cells grown under hypoxic over normoxic conditions (IC₅₀s = 0.019 and 5.1 μM, respectively).¹ Under hypoxic conditions, TH-302 undergoes a one-electron reduction to form an active radical intermediate that is then further reduced to form a DNA-intercalating hydroxylamine. Under normoxic conditions, the radical intermediate is quenched and induces reformation of the inactive nitroazole prodrug. TH-302 reduces survival of H460 and HT-29 cells in a clonogenic assay (IC₅₀s = 0.2 and 0.2 μM, respectively). In vivo, TH-302 (33 mg/kg per day) inhibits primary tumor growth by 41% in an MIA PaCa-2-RFP mouse orthotopic xenograft model. It inhibits tumor growth by greater than 40% in Calu-6 NSCLC, H82 small cell lung, A375 melanoma, PC-3 prostate, and BxPC-3 pancreatic cancer mouse xenograft models when administered at 50 mg/kg.²

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1. Duan, J.-X., Jiao, H., Kaizerman, J., et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J. Med. Chem. 51(8), 2412-2420 (2008).

2. Sun, J.D., Liu, Q., Wang, J., et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin. Cancer Res. 18(3), 758-770 (2012).