PR-104

PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs),[1] which is being researched as a potential anti-cancer therapeutic agent. It is a phosphate ester “pre-prodrug” that is rapidly converted to the HAP PR-104A in the body. PR-104A is in turn metabolised to reactive nitrogen mustard DNA crosslinking agents in hypoxic tissues such as found in solid tumours.[2][3] Following initial clinical studies,[4][5] it was discovered that PR-104A is also activated by the enzyme AKR1C3, independently of hypoxia.[6] Hypoxia in the bone marrow of patients with leukaemia,[7][8] and high activity of AKR1C3 in some leukaemia subtypes [9][10] has led to interest in clinical trials of PR-104 in relapsed refractory acute leukaemias.[11]

PR-104
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC14H20BrN4O12PS
Molar mass579.27 g·mol−1
3D model (JSmol)

References
  1. Wilson, William R.; Hay, Michael P. (1 June 2011). "Targeting hypoxia in cancer therapy". Nature Reviews. Cancer. 11 (6): 393–410. doi:10.1038/nrc3064. ISSN 1474-1768. PMID 21606941.
  2. Patterson, Adam V.; Ferry, Dianne M.; Edmunds, Shelley J.; Gu, Yongchuan; Singleton, Rachelle S.; Patel, Kashyap; Pullen, Susan M.; Hicks, Kevin O.; Syddall, Sophie P.; Atwell, Graham J.; Yang, Shangjin; Denny, William A.; Wilson, William R. (1 July 2007). "Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104". Clinical Cancer Research. 13 (13): 3922–3932. doi:10.1158/1078-0432.CCR-07-0478. PMID 17606726.
  3. Singleton, Rachelle S.; Guise, Christopher P.; Ferry, Dianne M.; Pullen, Susan M.; Dorie, Mary J.; Brown, J. Martin; Patterson, Adam V.; Wilson, William R. (1 May 2009). "DNA Cross-Links in Human Tumor Cells Exposed to the Prodrug PR-104A: Relationships to Hypoxia, Bioreductive Metabolism, and Cytotoxicity". Cancer Research. 69 (9): 3884–3891. doi:10.1158/0008-5472.CAN-08-4023. ISSN 0008-5472. PMID 19366798.
  4. Jameson, Michael B.; Rischin, Danny; Pegram, Mark; Gutheil, John; Patterson, Adam V.; Denny, William A.; Wilson, William R. (March 2010). "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 Chemotherapy and Pharmacology. 65 (4): 791–801. doi:10.1007/s00280-009-1188-1. ISSN 0344-5704. PMID 20012293.
  5. McKeage, Mark J; Gu, Yongchuan; Wilson, William R; Hill, Andrew; Amies, Karen; Melink, Teresa J; Jameson, Michael B (7 October 2011). "A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients". BMC Cancer. 11 (1): 432. doi:10.1186/1471-2407-11-432. ISSN 1471-2407. PMC 3205073. PMID 21982454.
  6. Guise, Christopher P.; Abbattista, Maria R.; Singleton, Rachelle S.; Holford, Samuel D.; Connolly, Joanna; Dachs, Gabi U.; Fox, Stephen B.; Pollock, Robert; Harvey, Justin; Guilford, Parry; Doñate, Fernando; Wilson, William R.; Patterson, Adam V. (15 February 2010). "The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3". Cancer Research. 70 (4): 1573–1584. doi:10.1158/0008-5472.CAN-09-3237. ISSN 0008-5472. PMID 20145130.
  7. Benito, Juliana; Shi, Yuexi; Szymanska, Barbara; Carol, Hernan; Boehm, Ingrid; Lu, Hongbo; Konoplev, Sergej; Fang, Wendy; Zweidler-McKay, Patrick A.; Campana, Dario; Borthakur, Gautam; Bueso-Ramos, Carlos; Shpall, Elizabeth; Thomas, Deborah A.; Jordan, Craig T.; Kantarjian, Hagop; Wilson, William R.; Lock, Richard; Andreeff, Michael; Konopleva, Marina (11 August 2011). "Pronounced Hypoxia in Models of Murine and Human Leukemia: High Efficacy of Hypoxia-Activated Prodrug PR-104". PLOS ONE. 6 (8): e23108. Bibcode:2011PLoSO...623108B. doi:10.1371/journal.pone.0023108. ISSN 1932-6203. PMC 3154919. PMID 21853076.
  8. Benito, Juliana; Zeng, Zhihong; Konopleva, Marina; Wilson, William R (1 August 2013). "Targeting hypoxia in the leukemia microenvironment". International Journal of Hematologic Oncology. 2 (4): 279–288. doi:10.2217/ijh.13.32. ISSN 2045-1393. PMC 3905090. PMID 24490034.
  9. Jamieson, Stephen M. F.; Gu, Yongchuan; Manesh, Donya Moradi; El-Hoss, Jad; Jing, Duohui; MacKenzie, Karen L.; Guise, Christopher P.; Foehrenbacher, Annika; Pullen, Susan M.; Benito, Juliana; Smaill, Jeffrey B.; Patterson, Adam V.; Mulaw, Medhanie A.; Konopleva, Marina; Bohlander, Stefan K.; Lock, Richard B.; Wilson, William R. (1 March 2014). "A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells". Biochemical Pharmacology. 88 (1): 36–45. doi:10.1016/j.bcp.2013.12.019. PMID 24434189.
  10. Manesh, Donya Moradi; El-Hoss, Jad; Evans, Kathryn; Richmond, Jennifer; Toscan, Cara E.; Bracken, Lauryn S.; Hedrick, Ashlee; Sutton, Rosemary; Marshall, Glenn M.; Wilson, William R.; Kurmasheva, Raushan T.; Billups, Catherine; Houghton, Peter J.; Smith, Malcolm A.; Carol, Hernan; Lock, Richard B. (3 September 2015). "AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia". Blood. 126 (10): 1193–1202. doi:10.1182/blood-2014-12-618900. ISSN 0006-4971. PMC 4559932. PMID 26116659.
  11. Konopleva, M.; Thall, P. F.; Yi, C. A.; 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, H. Q.; Feliu, J.; Lu, H.; Wei, C.; Wilson, W. R.; Melink, T. J.; Gutheil, J. C.; Andreeff, M.; Estey, E. H.; Kantarjian, H. (1 July 2015). "Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia". Haematologica. 100 (7): 927–934. doi:10.3324/haematol.2014.118455. ISSN 0390-6078. PMC 4486227. PMID 25682597.
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