| TH-302 | |
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N,N′-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester |
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Other names
HAP-302 |
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| Identifiers | |
| CAS number | 918633-87-1 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C9H16Br2N5O4P |
| Molar mass | 449.04 g mol−1 |
| (verify) (what is: /?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
TH-302 is an experimental cancer treatment that is in clinical development at Threshold Pharmaceuticals, Inc.[1] It is activated only at very low levels of oxygen (hypoxia).[2] Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia. TH-302 exploits the activation of a nitroazole prodrug by a process that involves a one electron reduction mediated by ubiquitous cellular reductases such as the NADPH cytochrome P450 to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide (SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions to the hydroxylamine (HA) followed by elimination, releasing the active drug and an azole derivative (AZ). This activation pathway is shown schematically below:
Phosphoramidate-based, DNA-crosslinking, bis-alkylator mustards have long been used successfully in cancer chemotherapy and include the prodrugs ifosfamide and cyclophosphamide. To demonstrate that known drugs of proven efficacy could serve as the basis of efficacious hypoxia activated prodrugs, the 2-nitroimidizole HAP of the active phosphoramidate bis-alkylator derived from ifosfamide was synthesized. The resulting compound, TH-281, had a high HCR (hypoxia cytotoxicity ratio), a quantitative assessment of its hypoxia selectivity. Subsequent structure-activity relationship (SAR) studies at Threshold showed that replacement of the chlorines in the alkylator portion of the prodrug with bromines improved potency about 10-fold. The final compound is TH-302.
TH-302 started a Phase 1 clinical trial in 2007 in various solid tumors.[3] The Phase 1 trial is a multi-center, open-label, dose-escalation study in patients with solid tumor cancers. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of TH-302 in patients with advanced solid tumors and to establish the appropriate dose to be tested in Phase 2 clinical trials. The secondary objectives of the trial include establishing the pharmacokinetics and assessing the anti-tumor activity of TH-302, as measured by objective response rate and duration of response, and to characterize the safety profile. Tumors will be evaluated at baseline and every eight weeks using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.