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
Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.	2011	21853076
A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients.	2011 Oct 7	21982454
PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours.	2012 Oct 25	23098625
The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104.	2013	24109591
Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling.	2013 Dec 27	24409417
Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.	2014 Feb	23845143
A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells.	2014 Mar 1	24434189
Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer.	2014 Nov	25193512
Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.	2015	25869917
Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.	2015 Jul	25682597
Biomarker of sensitivity to PR-104 in leukemia.	2015 Sep 3	26337349
AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.	2015 Sep 3	26116659
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.	2016 Mar	26811177
Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy.	2016 Sep 15	27453434
Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A.	2018 Aug	29630868

Patents

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:03:50 GMT 2023` Edited by `admin` on `Fri Dec 15 16:03:50 GMT 2023`
Record UNII	V16D2ZT7DT
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PR-104

Common Name

English

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

Systematic Name

English

PR 104 [WHO-DD]

Common 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