PR-104
{{Short description|Chemical compound}}
{{Drugbox
| IUPAC_name = [2-({2-[(2-Bromoethyl)[2-(methanesulfonyloxy)ethyl]amino]-3,5-dinitrophenyl}formamido)ethoxy]phosphonic acid
| image = PR-104 structure.svg
| width = 240
| tradename =
| legal_status =
| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 851627-62-8
| PubChem = 11455973
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| ChemSpiderID = 9630821
| ChEMBL =
| KEGG =
| UNII = V16D2ZT7DT
| C=14 | H=20 | Br=1 | N=4 | O=12 | P=1 | S=1
| molecular_weight =
| smiles = CS(=O)(=O)OCCN(CCBr)c1c(cc(cc1[N+](=O)[O-])[N+](=O)[O-])C(=O)NCCOP(=O)(O)O
| StdInChI = 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)
| StdInChIKey = GZSOKPMDWVRVMG-UHFFFAOYSA-N
}}
PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs),{{cite journal | vauthors = Wilson WR, Hay MP | title = Targeting hypoxia in cancer therapy | journal = Nature Reviews. Cancer | volume = 11 | issue = 6 | pages = 393–410 | date = June 2011 | pmid = 21606941 | doi = 10.1038/nrc3064 | s2cid = 36040922 }} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104 | journal = Clinical Cancer Research | volume = 13 | issue = 13 | pages = 3922–32 | date = July 2007 | pmid = 17606726 | doi = 10.1158/1078-0432.CCR-07-0478 | url = http://clincancerres.aacrjournals.org/content/13/13/3922.long | doi-access = free }}{{cite journal | vauthors = Singleton RS, Guise CP, Ferry DM, Pullen SM, Dorie MJ, Brown JM, Patterson AV, Wilson WR | display-authors = 6 | title = DNA cross-links in human tumor cells exposed to the prodrug PR-104A: relationships to hypoxia, bioreductive metabolism, and cytotoxicity | journal = Cancer Research | volume = 69 | issue = 9 | pages = 3884–91 | date = May 2009 | pmid = 19366798 | doi = 10.1158/0008-5472.CAN-08-4023 | url = http://cancerres.aacrjournals.org/content/69/9/3884.long | doi-access = free }}{{cite journal | vauthors = Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO | title = Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling | journal = Frontiers in Oncology | volume = 3 | issue = | pages = 314 | date = December 2013 | pmid = 24409417 | pmc = 3873531 | doi = 10.3389/fonc.2013.00314 | doi-access = free }} Following initial clinical studies,{{cite journal | vauthors = Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR | title = 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 | journal = Cancer Chemotherapy and Pharmacology | volume = 65 | issue = 4 | pages = 791–801 | date = March 2010 | pmid = 20012293 | doi = 10.1007/s00280-009-1188-1 | s2cid = 35209191 }}{{cite journal | vauthors = McKeage MJ, Gu Y, Wilson WR, Hill A, Amies K, Melink TJ, Jameson MB | title = A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients | journal = BMC Cancer | volume = 11 | issue = 1 | pages = 432 | date = October 2011 | pmid = 21982454 | pmc = 3205073 | doi = 10.1186/1471-2407-11-432 | doi-access = free }} it was discovered that PR-104A is also activated by the enzyme AKR1C3, independently of hypoxia.{{cite journal | vauthors = Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, Fox SB, Pollock R, Harvey J, Guilford P, Doñate F, Wilson WR, Patterson AV | display-authors = 6 | title = The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3 | journal = Cancer Research | volume = 70 | issue = 4 | pages = 1573–84 | date = February 2010 | pmid = 20145130 | doi = 10.1158/0008-5472.CAN-09-3237 | url = http://cancerres.aacrjournals.org/content/70/4/1573.long | doi-access = free }} Hypoxia in the bone marrow of patients with leukaemia,{{cite journal | vauthors = Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H, Konoplev S, Fang W, Zweidler-McKay PA, Campana D, Borthakur G, Bueso-Ramos C, Shpall E, Thomas DA, Jordan CT, Kantarjian H, Wilson WR, Lock R, Andreeff M, Konopleva M | display-authors = 6 | title = Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104 | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23108 | date = 11 August 2011 | pmid = 21853076 | pmc = 3154919 | doi = 10.1371/journal.pone.0023108 | bibcode = 2011PLoSO...623108B | doi-access = free }}{{cite journal | vauthors = Benito J, Zeng Z, Konopleva M, Wilson WR | title = Targeting hypoxia in the leukemia microenvironment | journal = International Journal of Hematologic Oncology | volume = 2 | issue = 4 | pages = 279–288 | date = August 2013 | pmid = 24490034 | pmc = 3905090 | doi = 10.2217/ijh.13.32 }} and high activity of AKR1C3 in some leukaemia subtypes {{cite journal | vauthors = Jamieson SM, Gu Y, Manesh DM, El-Hoss J, Jing D, Mackenzie KL, Guise CP, Foehrenbacher A, Pullen SM, Benito J, Smaill JB, Patterson AV, Mulaw MA, Konopleva M, Bohlander SK, Lock RB, Wilson WR | display-authors = 6 | title = A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells | journal = Biochemical Pharmacology | volume = 88 | issue = 1 | pages = 36–45 | date = March 2014 | pmid = 24434189 | doi = 10.1016/j.bcp.2013.12.019 }}{{cite journal | vauthors = 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 | display-authors = 6 | title = AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia | journal = Blood | volume = 126 | issue = 10 | pages = 1193–202 | date = September 2015 | pmid = 26116659 | pmc = 4559932 | doi = 10.1182/blood-2014-12-618900 }}{{cite journal | vauthors = Abbattista MR, Ashoorzadeh A, Guise CP, Mowday AM, Mittra R, Silva S, Hicks KO, Bull MR, Jackson-Patel V, Lin X, Prosser GA, Lambie NK, Dachs GU, Ackerley DF, Smaill JB, Patterson AV | display-authors = 6 | title = Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3 | journal = Pharmaceuticals | volume = 14 | issue = 12 | date = November 2021 | page = 1231 | pmid = 34959631 | pmc = 8707548 | doi = 10.3390/ph14121231 | doi-access = free }} has led to interest in clinical trials of PR-104 in relapsed refractory acute leukaemias.{{cite journal | vauthors = 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 | display-authors = 6 | title = Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia | journal = Haematologica | volume = 100 | issue = 7 | pages = 927–34 | date = July 2015 | pmid = 25682597 | pmc = 4486227 | doi = 10.3324/haematol.2014.118455 }}{{cite journal | vauthors = Phillips RM | title = Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs | journal = Cancer Chemotherapy and Pharmacology | volume = 77 | issue = 3 | pages = 441–57 | date = March 2016 | pmid = 26811177 | pmc = 4767869 | doi = 10.1007/s00280-015-2920-7 }}