PR-104

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H20BrN4O12PS
Molecular Weight	579.271
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(=O)(=O)OCCN(CCBr)C1=C(C=C(C=C1C(=O)NCCOP(O)(O)=O)[N+]([O-])=O)[N+]([O-])=O

InChI

InChIKey=GZSOKPMDWVRVMG-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C14H20BrN4O12PS
Molecular Weight	579.271
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://adisinsight.springer.com/drugs/800023717 | https://www.ncbi.nlm.nih.gov/pubmed/23098625 | https://www.ncbi.nlm.nih.gov/pubmed/21982454

PR-104 is a phosphate ester dinitrobenzamide mustard pre-prodrug that is rapidly hydrolyzed systemically to PR-104A, a bioreductive prodrug. PR-104A is in turn activated via reduction by NADPH:cytochrome P450 oxidoreductase and other one-electron reductases in hypoxic cells, and by aldo-keto reductase 1C3 (AKR1C3) independently of oxygen, to the corresponding hydroxylamine (PR-104H) and amine (PR-104M) metabolites. Subsequently, these reactive nitrogen mustards crosslink DNA and cause cytotoxicity in cells. PR-104 is known to have preclinical anti-tumor activity in human tumor xenograft models as mono-therapy and in combination with radiotherapy and chemotherapy. Thrombocytopenia, and to a lesser extent neutropenia, was the dose-limiting toxicity of weekly PR-104. Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity in patients with advanced solid tumors. PR-104 had been in phase II clinical trial for the treatment of acute myeloid leukemia.

Originator

Approval Year

PubMed

Title	Date	PubMed
Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A.	2018-08	29630868
Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy.	2016-09-15	27453434
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.	2016-03	26811177
Biomarker of sensitivity to PR-104 in leukemia.	2015-09-03	26337349
AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.	2015-09-03	26116659
Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.	2015-07	25682597
Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.	2015	25869917
Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer.	2014-11	25193512
A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells.	2014-03-01	24434189
Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.	2014-02	23845143
Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling.	2013-12-27	24409417
The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104.	2013	24109591
PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours.	2012-10-25	23098625
A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients.	2011-10-07	21982454
Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.	2011	21853076

Patents

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:17:53 GMT 2025` Edited by `admin` on `Mon Mar 31 18:17:53 GMT 2025`
Record UNII	V16D2ZT7DT
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PR 104 [WHO-DD]

Preferred Name

English

PR-104

Common Name

English

((2-BROMOETHYL)-2,4-DINITRO-6-(((2-(PHOSPHONOOXY)ETHYL)AMINO)-CARBONYL)ANILINO)ETHYL METHANESULPHONATE

Systematic Name

English

((2-BROMOETHYL)-2,4-DINITRO-6-(((2-(PHOSPHONOOXY)ETHYL)AMINO)-CARBONYL)ANILINO)ETHYL METHANESULFONATE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C274