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PR-104

PR-104 is a non-toxic, small-molecule, hypoxia-activated, 3,5-dinitrobenzamide nitrogen mustard pre-prodrug with potential antitumor activity. Upon intravenous administration, PR-104 is converted by systemic phosphatases to the alcohol intermediate PR-104A, which is reduced to form the active DNA-crosslinking mustard species hydroxylamine PR-104H intracellularly under hypoxic conditions. PR-104H specifically crosslinks hypoxic tumor cell DNA, resulting in the inhibition of DNA repair and synthesis, cell-cycle arrest, and apoptosis in susceptible hypoxic tumor cell populations while sparing normoxic tissues. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

PR-104 is a novel pre-prodrug of the dinitrobenzamide mustard class, with selective toxicity to hypoxic tumor cells. PR-104 is a water-soluble phosphate ester that is hydrolyzed by phosphatases to the corresponding alcohol metabolite, a more lipophilic prodrug referred to as PR-104A. PR-104A is reduced selectively under hypoxic conditions to a hydroxylamine metabolite, PR-104H, which is a cytotoxic nitrogen mustard alkylating agent. PR-104H exerts its cytotoxic effect through the formation of DNA interstrand crosslinks. In xenograft models, PR-104 demonstrated anti-tumor activity as monotherapy against several human solid tumors (SiHa cervical, HT29 colon and H460 NSCLC). see http://www.proacta.com/trials/trials.htm.

Activation of pathway of PR-104

Source: Michael Jameson1, Danny Rischin2, Mark Pegram3, John Gutheil4, Adam Patterson5, William Denny5, William Wilson5: A Phase I Pharmacokinetic Study of PR-104, a Hypoxia–Activated Nitrogen Mustard Prodrug, in Patients with Solid. www.proacta.com/assets/pdfs/ASCO_STUDY_1001_2008.pdf 

Current developer:    Proacta Inc

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2. Gu, Yongchuan; Atwell, Graham J.; Wilson, William R. Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans. Drug Metabolism and Disposition (2010), 38(3), 498-508. CODEN: DMDSAI ISSN:0090-9556. CAN 152:540913 AN 2010:327864

3. 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; Donate, Fernando; Wilson, William R.; Patterson, Adam V. The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3. Cancer Research (2010), 70(4), 1573-1584. CODEN: CNREA8 ISSN:0008-5472. CAN 152:469295 AN 2010:192736

4. Jameson, Michael B.; Rischin, Danny; Pegram, Mark; Gutheil, John; Patterson, Adam V.; Denny, William A.; Wilson, William R. 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 (2010), 65(4), 791-801. CODEN: CCPHDZ ISSN:0344-5704. AN 2010:80563

5. Cairns, Rob A.; Bennewith, Kevin L.; Graves, Edward E.; Giaccia, Amato J.; Chang, Daniel T.; Denko, Nicholas C. Pharmacologically Increased Tumor Hypoxia can be Measured by 18F-Fluoroazomycin Arabinoside Positron Emission Tomography and Enhances Tumor Response to Hypoxic Cytotoxin PR-104. Clinical Cancer Research (2009), 15(23), 7170-7174. CODEN: CCREF4 ISSN:1078-0432. AN 2009:1504923

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8. Gu, Yongchuan; Wilson, William R. Rapid and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of the novel anticancer agent PR-104 and its major metabolites in human plasma: Application to a pharmacokinetic study. Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2009), 877(27), 3181-3186. CODEN: JCBAAI ISSN:1570-0232. CAN 151:417407 AN 2009:1125172

9. Gu, Yongchuan; Patterson, Adam V.; Atwell, Graham J.; Chernikova, Sophia B.; Brown, J. Martin; Thompson, Larry H.; Wilson, William R. Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A. Molecular Cancer Therapeutics (2009), 8(6), 1714-1723. CODEN: MCTOCF ISSN:1535-7163. CAN 151:235958 AN 2009:706356

10. Singleton, Rachelle S.; Guise, Christopher P.; Ferry, Dianne M.; Pullen, Susan M.; Dorie, Mary J.; Brown, J. Martin; Patterson, Adam V.; Wilson, William R. DNA Cross-Links in Human Tumor Cells Exposed to the Prodrug PR-104A: Relationships to Hypoxia, Bioreductive Metabolism, and Cytotoxicity. Cancer Research (2009), 69(9), 3884-3891. CODEN: CNREA8 ISSN:0008-5472. CAN 151:48754 AN 2009:517726

11. Liu, Shie-Chau; Ahn, G.-One; Kioi, Mitomu; Dorie, Mary-Jo; Patterson, Adam V.; Brown, J. Martin. Optimized Clostridium-Directed Enzyme Prodrug Therapy Improves the Antitumor Activity of the Novel DNA Cross-Linking Agent PR-104. Cancer Research (2008), 68(19), 7995-8003. CODEN: CNREA8 ISSN:0008-5472. CAN 149:549429 AN 2008:1195243

12. Tredan, Olivier; Grantab, Rama; Dumontet, Charles. Can tumor hypoxia be turned into a chemotherapeutic advantage? Bulletin du Cancer (2008), 95(5), 528-534. CODEN: BUCABS ISSN:0007-4551. CAN 149:282333 AN 2008:791703

13. Patterson, Adam Vorn; Wilson, William Robert. Use of PR-104 or a related nitrobenzene derivative in combination with gemcitabine for cancer treatment. PCT Int. Appl. (2008), 31pp. CODEN: PIXXD2 WO 2008033039 A1 20080320 CAN 148:347331 AN 2008:353264

14. Patterson, Adam Vorn; Cossum, Paul Adrian. PR-104 or related compound combination with bevacizumab for cancer treatment. PCT Int. Appl. (2008), 37pp. CODEN: PIXXD2 WO 2008033041 A1 20080320 CAN 148:347326 AN 2008:352906

15. Patterson, Adam Vorn; Wilson, William Robert. Nitrobenzene derivative combination with docetaxel for the treatment of cancer. U.S. Pat. Appl. Publ. (2008), 26 pp. CODEN: USXXCO US 2008064665 A1 20080313 CAN 148:347317 AN 2008:321951

16. Helsby, Nuala A.; Goldthorpe, Michael A.; Tang, Magdalene H. Y.; Atwell, Graham J.; Smith, Eileen M.; Wilson, William R.; Tingle, Malcolm D. Influence of mustard group structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)-3,5-dinitrobenzamide 2-mustard prodrugs. Drug Metabolism and Disposition (2008), 36(2), 353-360. CODEN: DMDSAI ISSN:0090-9556. CAN 148:345675 AN 2008:128789

17. Hicks, Kevin O.; Myint, Hilary; Patterson, Adam V.; Pruijn, Frederik B.; Siim, Bronwyn G.; Patel, Kashyap; Wilson, William. R. Oxygen Dependence and Extravascular Transport of Hypoxia-Activated Prodrugs: Comparison of the Dinitrobenzamide Mustard PR-104A and Tirapazamine. International Journal of Radiation Oncology, Biology, Physics (2007), 69(2), 560-571. CODEN: IOBPD3 ISSN:0360-3016. CAN 148:112416 AN 2007:1039164

18. Patel, Kashyap; Lewiston, David; Gu, Yongchuan; Hicks, Kevin O.; Wilson, William R. Analysis of the hypoxia-activated dinitrobenzamide mustard phosphate pre-prodrug PR-104 and its alcohol metabolite PR-104A in plasma and tissues by liquid chromatography-mass spectrometry. Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2007), 856(1-2), 302-311. CODEN: JCBAAI ISSN:1570-0232. CAN 147:461512 AN 2007:996381

19. Guise, Chris P.; Wang, Anderson T.; Theil, Anke; Bridewell, David J.; Wilson, William R.; Patterson, Adam V. Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: A role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochemical Pharmacology (2007), 74(6), 810-820. CODEN: BCPCA6 ISSN:0006-2952. CAN 147:439451 AN 2007:897047

20. 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. Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104. Clinical Cancer Research (2007), 13(13), 3922-3932. CODEN: CCREF4 ISSN:1078-0432. CAN 147:534141 AN 2007:718552

21. Yang, Shangjin; Atwell, Graham J.; Denny, William A. Synthesis of asymmetric halomesylate mustards with aziridineethanol/alkali metal halides: application to an improved synthesis of the hypoxia prodrug PR-104. Tetrahedron (2007), 63(25), 5470-5476. CODEN: TETRAB ISSN:0040-4020. CAN 147:166022 AN 2007:556217

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