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][4] Following initial clinical studies,[5][6] it was discovered that PR-104A is also activated by the enzyme AKR1C3, independently of hypoxia.[7] Hypoxia in the bone marrow of patients with leukaemia,[8][9] and high activity of AKR1C3 in some leukaemia subtypes [10][11][12] has led to interest in clinical trials of PR-104 in relapsed refractory acute leukaemias.[13][14]

PR-104
Identifiers
  • [2-({2-[(2-Bromoethyl)[2-(methanesulfonyloxy)ethyl]amino]-3,5-dinitrophenyl}formamido)ethoxy]phosphonic acid
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H20BrN4O12PS
Molar mass579.27 g·mol−1
3D model (JSmol)
  • CS(=O)(=O)OCCN(CCBr)c1c(cc(cc1[N+](=O)[O-])[N+](=O)[O-])C(=O)NCCOP(=O)(O)O
  • InChI=1S/C14H20BrN4O12PS/c1-33(28,29)31-7-5-17(4-2-15)13-11(14(20)16-3-6-30-32(25,26)27)8-10(18(21)22)9-12(13)19(23)24/h8-9H,2-7H2,1H3,(H,16,20)(H2,25,26,27)
  • Key:GZSOKPMDWVRVMG-UHFFFAOYSA-N

References
  1. Wilson WR, Hay MP (June 2011). "Targeting hypoxia in cancer therapy". Nature Reviews. Cancer. 11 (6): 393–410. doi:10.1038/nrc3064. PMID 21606941. S2CID 36040922.
  2. Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, et al. (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): 3922–32. doi:10.1158/1078-0432.CCR-07-0478. PMID 17606726.
  3. Singleton RS, Guise CP, Ferry DM, Pullen SM, Dorie MJ, Brown JM, et al. (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): 3884–91. doi:10.1158/0008-5472.CAN-08-4023. PMID 19366798.
  4. Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO (December 2013). "Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling". Frontiers in Oncology. 3: 314. doi:10.3389/fonc.2013.00314. PMC 3873531. PMID 24409417.
  5. Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR (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. PMID 20012293. S2CID 35209191.
  6. McKeage MJ, Gu Y, Wilson WR, Hill A, Amies K, Melink TJ, Jameson MB (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. PMC 3205073. PMID 21982454.
  7. Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, et al. (February 2010). "The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3". Cancer Research. 70 (4): 1573–84. doi:10.1158/0008-5472.CAN-09-3237. PMID 20145130.
  8. Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H, et al. (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. PMC 3154919. PMID 21853076.
  9. Benito J, Zeng Z, Konopleva M, Wilson WR (August 2013). "Targeting hypoxia in the leukemia microenvironment". International Journal of Hematologic Oncology. 2 (4): 279–288. doi:10.2217/ijh.13.32. PMC 3905090. PMID 24490034.
  10. Jamieson SM, Gu Y, Manesh DM, El-Hoss J, Jing D, Mackenzie KL, et al. (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.
  11. Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, et al. (September 2015). "AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia". Blood. 126 (10): 1193–202. doi:10.1182/blood-2014-12-618900. PMC 4559932. PMID 26116659.
  12. Abbattista MR, Ashoorzadeh A, Guise CP, Mowday AM, Mittra R, Silva S, et al. (November 2021). "Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3". Pharmaceuticals. 14 (12): 1231. doi:10.3390/ph14121231. PMC 8707548. PMID 34959631.
  13. Konopleva M, Thall PF, Yi CA, Borthakur G, Coveler A, Bueso-Ramos C, et al. (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): 927–34. doi:10.3324/haematol.2014.118455. PMC 4486227. PMID 25682597.
  14. Phillips RM (March 2016). "Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs". Cancer Chemotherapy and Pharmacology. 77 (3): 441–57. doi:10.1007/s00280-015-2920-7. PMC 4767869. PMID 26811177.
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