TH-302 --- Hypoxia-activated Pro-drug

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.

Product information

CAS Number: 918633-87-1

Molecular Weight: 449.04

Formula: C9H16Br2N5O4P

Synonym:

Evofosfamide

Chemical Name: (1-methyl-2-nitro-1H-imidazol-5-yl)methyl N,N’-bis(2-bromoethyl)phosphordiamidate

Smiles: CN1C(=NC=C1COP(=O)(NCCBr)NCCBr)[N+]([O-])=O

InChiKey: UGJWRPJDTDGERK-UHFFFAOYSA-N

InChi: InChI=1S/C9H16Br2N5O4P/c1-15-8(6-12-9(15)16(17)18)7-20-21(19,13-4-2-10)14-5-3-11/h6H,2-5,7H2,1H3,(H2,13,14,19)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 50 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

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.

References:

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. Hu J, et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. (2010) Blood. 116(9):1524-7.
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. Meng F, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. (2012) Mol Cancer Ther. 11(3):740-51.
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. 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.

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