PR-104
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Formula | C14H20BrN4O12PS |
Molar mass | 579.27 g·mol−1 |
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PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs), which is being researched as a potential anti-cancer therapeutic agent. It is an advanced nitrogen mustard prodrug which is designed to be selectively converted to its cytotoxic active form only inside hypoxic tissues such as that found in solid tumours.[1][2][3] Following initial pre-clinical studies it was serendipitously discovered that this conversion happens at particularly high efficiency in tumours associated with acute myeloid leukemia and acute lymphoblastic leukemia, and subsequent clinical trials have focused on developing PR-104 as a specific treatment targeted at these cancer subtypes.[4][5][6]
References
- ^ Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, Pullen SM, Hicks KO, Syddall SP, Atwell GJ, Yang S, Denny WA, Wilson WR. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res. 2007 Jul 1;13(13):3922-32. PMID 17606726
- ^ Helsby NA, Goldthorpe MA, Tang MH, Atwell GJ, Smith EM, Wilson WR, Tingle MD. Influence of mustard group structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)-3,5-dinitrobenzamide 2-mustard prodrugs. Drug Metab Dispos. 2008 Feb;36(2):353-60. PMID 17998296
- ^ Guise CP, Mowday AM, Ashoorzadeh A, Yuan R, Lin WH, Wu DH, Smaill JB, Patterson AV, Ding K. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin J Cancer. 2014 Feb;33(2):80-6. doi: 10.5732/cjc.012.10285. PMID 23845143
- ^ Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR. A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors. Cancer Chemother Pharmacol. 2010 Mar;65(4):791-801. doi: 10.1007/s00280-009-1188-1. PMID 20012293
- ^ Konopleva M, Thall PF, Yi CA, Borthakur G, Coveler A, Bueso-Ramos C, Benito J, Konoplev S, Gu Y, Ravandi F, Jabbour E, Faderl S, Thomas D, Cortes J, Kadia T, Kornblau S, Daver N, Pemmaraju N, Nguyen HQ, Feliu J, Lu H, Wei C, Wilson WR, Melink TJ, Gutheil JC, Andreeff M, Estey EH, Kantarjian H. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica. 2015 Jul;100(7):927-34. doi: 10.3324/haematol.2014.118455. PMID 25682597
- ^ Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, Hedrick A, Sutton R, Marshall GM, Wilson WR, Kurmasheva RT, Billups C, Houghton PJ, Smith MA, Carol H, Lock RB. AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood. 2015 Sep 3;126(10):1193-202. doi: 10.1182/blood-2014-12-618900. PMID 26116659