Delving into the Latest Updates on PR-104 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PR 104, SN-29244

Target

DNA

Action

inhibitors

Mechanism

DNA inhibitors(DNA inhibitors), DNA alkylating agents

Therapeutic Areas

NeoplasmsImmune System DiseasesDigestive System Disorders+ [2]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAdvanced Hepatocellular CarcinomaAdvanced Lung Non-Small Cell Carcinoma+ [4]

Originator Organization

Proacta, Inc.

Active Organization-

Inactive Organization

Proacta, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC14H20BrN4O12PS

InChIKeyGZSOKPMDWVRVMG-UHFFFAOYSA-N

CAS Registry851627-62-8

The current understanding of PR104 justifies the evaluation of PR104 in subjects with relapsed/refractory AML and ALL. These include:
* Hypoxia. Leukemic bone marrow is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Myelotoxicity as the primary toxicity at MTD. In prior clinical studies in subjects with solid tumors PR104 has demonstrated myelotoxicity as the primary toxicity. This observation suggests that PR104 will exert a similar effect on leukemic cells.
* AKR1C3. AML has been reported to exhibit high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic leukemic cells.
* Preclinical data. PR104 has demonstrated impressive activity in an initial study using primary human ALL in a mouse model.
The initial dose finding phase of the study will provide estimates of the activity and toxicity of PR104 in subjects with refractory/relapsed AML, and determine the optimal individualized dose to give each subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). Once a potentially beneficial dose has been determined, an expanded cohort of subjects with AML or ALL will receive PR104 at a uniform dose. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity and acceptable safety in AML to warrant future phase II or phase III studies in this indication.
Primary objectives
* Determine the toxicities and recommended dose of PR104 when administered IV to subjects with relapsed/refractory AML and ALL.
Secondary objectives
* Evaluate the pharmacokinetics (PK) of PR104 and a series of PR104 metabolites
* Evaluate any anti-tumor effects of PR104
* Evaluate the expression of AKR1C3 in bone marrow and leukemic cells
* Evaluate potential biomarkers of hypoxia

Start Date01 Jan 2010

Sponsor / Collaborator

Proacta, Inc.

NCT00862082

/ TerminatedPhase 1/2

A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
* Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment.
* Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
* Aldo-keto reductase 1C3 (AKR1C3). HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
* Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
Primary objectives
* Phase I: Determine the maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
* Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
Secondary objectives
* Evaluate survival
* Evaluate Progression Free Survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics (PK) of sorafenib, PR104 and PR104 metabolites
* Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

Start Date01 Mar 2009

Sponsor / Collaborator

Proacta, Inc.

NCT00862134

/ TerminatedPhase 2

A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer

The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:
* Aldo-keto reductase 1C3 (AKR1C3). NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.
* Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic positron emission tomography (PET) imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.
* Manageable toxicity. PR104 and docetaxel with Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (MTD) has been identified and the major toxicities of this combination are understood.
The current study will provide an estimate of the activity of PR104 in subjects with NSCLC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.
Primary objectives
• Estimate the response rate (RR) of PR104/docetaxel
Secondary objectives
* Evaluate survival
* Evaluate progression free survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics of PR104 and its metabolites
* Evaluate the pharmacokinetics of docetaxel
* Evaluate the tumor hypoxia using 18F-fluoromisonidazole (18F-MISO) PET imaging
* Collect diagnostic biopsy samples for the determination of AKR1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

Start Date01 Mar 2009

Sponsor / Collaborator

Proacta, Inc.

100 Clinical Results associated with PR-104

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100 Translational Medicine associated with PR-104

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100 Patents (Medical) associated with PR-104

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37

Literatures (Medical) associated with PR-104

01 Jul 2022·Cancer gene therapyQ2 · MEDICINE

Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411NTR leading to therapeutic benefit

Q2 · MEDICINE

Article

Author: Smaill, Jeff B ; Mowday, Alexandra M ; Li, Dan ; Ashoorzadeh, Amir ; Syddall, Sophie P ; Bai, Sally Y ; Singleton, Dean C ; Guise, Chris P ; Wilson, William R ; Patterson, Adam V

Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411^NTR in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411^NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411^NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411^NTR with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.

01 Aug 2018·Biochemical pharmacologyQ2 · MEDICINE

Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A

Q2 · MEDICINE

Article

Author: Gu, Yongchuan ; Wilson, William R ; Liyanage, H D Sarath ; Stornetta, Alessia ; Sturla, Shana J ; Danielli, Sara ; Deng, Kai-Cheng Kieren

PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R² = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.

20 Mar 2017·Chemical research in toxicologyQ3 · MEDICINE

DNA Adduct Profiles Predict in Vitro Cell Viability after Treatment with the Experimental Anticancer Prodrug PR104A

Q3 · MEDICINE

Article

Author: Balbo, Silvia ; Gossner, Frederike ; Sturla, Shana J. ; Villalta, Peter W. ; Stornetta, Alessia ; Wilson, William R.

PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed. Use of this SILAM-based approach supported simultaneous relative quantitation of 33 PR104A-derived DNA adducts in the same sample, which allowed testing of the hypothesis that the enhanced cytotoxicity, observed by preconditioning cells with the transcription-activating isothiocyanate sulforaphane, is induced by an increased level of DNA adducts induced by PR104H and PR104M, but not PR104A. By applying the new SILAM-SRM approach, we found a 2.4-fold increase in the level of DNA adducts induced by PR104H and PR104M in HT-29 cells preconditioned with sulforaphane and a corresponding 2.6-fold increase in cytotoxicity. These results suggest that DNA adduct levels correlate with drug potency and underly the possibility of monitoring PR104A-derived DNA adducts as biomarkers of efficacy.

100 Deals associated with PR-104

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External Link

KEGG	Wiki	ATC	Drug Bank
-	PR-104	-	DB05968

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Refractory Acute Leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Refractory acute myeloid leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Advanced Hepatocellular Carcinoma	Phase 2	United States	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Hong Kong	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Singapore	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Taiwan Province	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	United States	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Canada	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	New Zealand	Proacta, Inc.	01 Mar 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01037556 (ASCO2013)	Phase 1/2	refractory acute lymphoid leukemia in relapse	50	PR104	qwdzjvdmps(iqfuvubrcg) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) bavsijzlxl (kvobqxvdxr ) View more	-	20 May 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	Docetaxel (Docetaxel)	zcejvnyikh = gpbiragofs kxhmygkrkh (pfodvokmcz, cyjiwakdny - bulpsvwdnx) View more	-	10 Jan 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	PR104+Docetaxel (PR104 + Docetaxel)	zcejvnyikh = gzfszkixrt kxhmygkrkh (pfodvokmcz, xlulovptfo - tvguijkuso) View more	-	10 Jan 2013
NCT00544674 (CTgov)	Phase 2	Recurrent Lung Small Cell Carcinoma	5	F-18-fluoromisonidazole+PR104	amxtyfmokp = bfhhwuhrad uhfwbyinuv (zmbqhjsset, hytflihfrx - ycexzvfssq) View more	-	07 Jul 2011
ASCO2010	Phase 1	Solid tumor	26	PR104	zgxcefeuir(lmbpysdsaj) = xwdhlkfhdp ukddsdrxae (lbxuotmmgt, 0.11)	-	20 May 2010
ASCO2008	Phase 1	Advanced cancer	23	PR-104 + Gemcitabine	xisixijsgv(scybwvfpkm) = kguxpzoybb xrdcmlbryu (lzbofqixid )	-	20 May 2008
ASCO2008	Phase 1	Solid tumor	13	PR-104	ydtatfplhu(njblhopzyb) = zjrcpdjxxi igymmdwkiw (nvondhlmjr )	-	20 May 2008
ASCO2008	Phase 1	Solid tumor	-	PR-104	bisialpgly(dailwyxxfh) = onbkrzffwb tiysiubkpt (jcclmwbvgc )	-	20 May 2008