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MedKoo CAT#: 202901
Description: Evofosfamide, also known as TH-302, is a hypoxia-activated prodrug consisting of a 2-nitroimidazole phosphoramidate conjugate with potential antineoplastic activity. The 2-nitroimidazole moiety of hypoxia-activated prodrug TH-302 acts as a hypoxic trigger, releasing the DNA-alkylating dibromo isophosphoramide mustard moiety within hypoxic regions of tumors. Normoxic tissues may be spared due to the hypoxia-specific activity of this agent, potentially reducing systemic toxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI).
MedKoo Cat#: 202901
Chemical Formula: C9H16Br2N5O4P
Exact Mass: 446.93067
Molecular Weight: 449.04
Elemental Analysis: C, 24.07; H, 3.59; Br, 35.59; N, 15.60; O, 14.25; P, 6.90
Synonym: TH302; TH 302; TH-302. Evofosfamide
IUPAC/Chemical Name: Phosphorodiamidic acid, N,N'-bis(2-bromoethyl)-, (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester.
InChi Key: UGJWRPJDTDGERK-UHFFFAOYSA-N
InChi Code: 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)
SMILES Code: O=P(NCCBr)(NCCBr)OCC1=CN=C([N+]([O-])=O)N1C
According to wikipedia.com, TH-302 is an experimental anticancer agent that is in clinical development at Threshold Pharmaceuticals, Inc. It is activated only at very low levels of oxygen (hypoxia). 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).
TH-302 started a Phase 1 clinical trial in 2007 in various solid tumors. 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.
1: Saggar JK, Tannock IF. Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy. Int J Cancer. 2014 Jun 1;134(11):2726-34. doi: 10.1002/ijc.28595. Epub 2013 Dec 13. PubMed PMID: 24338277.
2: Portwood S, Lal D, Hsu YC, Vargas R, Johnson MK, Wetzler M, Hart CP, Wang ES. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res. 2013 Dec 1;19(23):6506-19. doi: 10.1158/1078-0432.CCR-13-0674. Epub 2013 Oct 2. PubMed PMID: 24088735.
3: Hu J, Van Valckenborgh E, Xu D, Menu E, De Raeve H, De Bryune E, Xu S, Van Camp B, Handisides D, Hart CP, Vanderkerken K. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro. Mol Cancer Ther. 2013 Sep;12(9):1763-73. doi: 10.1158/1535-7163.MCT-13-0123. Epub 2013 Jul 5. PubMed PMID: 23832122.
4: CÃ¡rdenas-RodrÃguez J, Li Y, Galons JP, Cornnell H, Gillies RJ, Pagel MD, Baker AF. Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model. Magn Reson Imaging. 2012 Sep;30(7):1002-9. doi: 10.1016/j.mri.2012.02.015. Epub 2012 May 1. PubMed PMID: 22554971; PubMed Central PMCID: PMC3402593.
5: Liu Q, Sun JD, Wang J, Ahluwalia D, Baker AF, Cranmer LD, Ferraro D, Wang Y, Duan JX, Ammons WS, Curd JG, Matteucci MD, Hart CP. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules. Cancer Chemother Pharmacol. 2012 Jun;69(6):1487-98. doi: 10.1007/s00280-012-1852-8. Epub 2012 Mar 2. PubMed PMID: 22382881; PubMed Central PMCID: PMC3985381.
6: Jung D, Jiao H, Duan JX, Matteucci M, Wang R. Metabolism and excretion of TH-302 in dogs. Xenobiotica. 2012 Jul;42(7):687-700. doi: 10.3109/00498254.2011.650234. Epub 2012 Feb 21. PubMed PMID: 22352389.
7: Sun JD, Liu Q, Wang J, Ahluwalia D, Ferraro D, Wang Y, Duan JX, Ammons WS, Curd JG, Matteucci MD, Hart CP. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin Cancer Res. 2012 Feb 1;18(3):758-70. doi: 10.1158/1078-0432.CCR-11-1980. Epub 2011 Dec 19. PubMed PMID: 22184053.
8: Meng F, Evans JW, Bhupathi D, Banica M, Lan L, Lorente G, Duan JX, Cai X, Mowday AM, Guise CP, Maroz A, Anderson RF, Patterson AV, Stachelek GC, Glazer PM, Matteucci MD, Hart CP. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther. 2012 Mar;11(3):740-51. doi: 10.1158/1535-7163.MCT-11-0634. Epub 2011 Dec 6. PubMed PMID: 22147748.
9: Jung D, Jiao H, Duan JX, Matteucci M, Wang R. Metabolism, pharmacokinetics and excretion of a novel hypoxia activated cytotoxic prodrug, TH-302, in rats. Xenobiotica. 2012 Apr;42(4):372-88. doi: 10.3109/00498254.2011.622810. Epub 2011 Oct 17. PubMed PMID: 22004352.
10: Jung D, Lin L, Jiao H, Cai X, Duan JX, Matteucci M. Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys. Cancer Chemother Pharmacol. 2012 Mar;69(3):643-54. doi: 10.1007/s00280-011-1741-6. Epub 2011 Oct 1. PubMed PMID: 21964906.