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

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.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

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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33

Literatures (Medical) associated with PR-104

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.

01 Sep 2016·Biochemical pharmacologyQ2 · MEDICINE

Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy

Q2 · MEDICINE

Article

Author: Guise, Christopher P ; Flanagan, Jack U ; Williams, Elsie M ; Copp, Janine N ; Silva, Shevan ; Bull, Matthew R ; Smaill, Jeff B ; Ashoorzadeh, Amir ; Anderson, Robert F ; Mowday, Alexandra M ; Abbattista, Maria R ; Ackerley, David F ; Patterson, Adam V

The clinical stage anti-cancer agent PR-104 has potential utility as a cytotoxic prodrug for exogenous bacterial nitroreductases expressed from replicating vector platforms. However substrate selectivity is compromised due to metabolism by the human one- and two-electron oxidoreductases cytochrome P450 oxidoreductase (POR) and aldo-keto reductase 1C3 (AKR1C3). Using rational drug design we developed a novel mono-nitro analog of PR-104A that is essentially free of this off-target activity in vitro and in vivo. Unlike PR-104A, there was no biologically relevant cytotoxicity in cells engineered to express AKR1C3 or POR, under aerobic or anoxic conditions, respectively. We screened this inert prodrug analog, SN34507, against a type I bacterial nitroreductase library and identified E. coli NfsA as an efficient bioactivator using a DNA damage response assay and recombinant enzyme kinetics. Expression of E. coli NfsA in human colorectal cancer cells led to selective cytotoxicity to SN34507 that was associated with cell cycle arrest and generated a robust 'bystander effect' at tissue-like cell densities when only 3% of cells were NfsA positive. Anti-tumor activity of SN35539, the phosphate pre-prodrug of SN34507, was established in 'mixed' tumors harboring a minority of NfsA-positive cells and demonstrated marked tumor control following heterogeneous suicide gene expression. These experiments demonstrate that off-target metabolism of PR-104 can be avoided and identify the suicide gene/prodrug partnership of E. coli NfsA/SN35539 as a promising combination for development in armed vectors.

03 Sep 2015·BloodQ1 · MEDICINE

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

Q1 · MEDICINE

Article

Author: Marshall, Glenn M. ; Carol, Hernan ; Lock, Richard B. ; Billups, Catherine ; Kurmasheva, Raushan T. ; Evans, Kathryn ; Toscan, Cara E. ; Wilson, William R. ; Smith, Malcolm A. ; Sutton, Rosemary ; Bracken, Lauryn S. ; Hedrick, Ashlee ; El-Hoss, Jad ; Richmond, Jennifer ; Moradi Manesh, Donya ; Houghton, Peter J.

Key Points:

PR-104 represents a potential novel treatment for relapsed/refractory T-ALL. AKR1C3 expression could be used as a biomarker to select patients who may respond to PR-104 in prospective clinical trials.

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	US	Proacta, Inc.	01 Jan 2010
Refractory Acute Leukemia	Phase 2	US	Proacta, Inc.	01 Jan 2010
Refractory acute myeloid leukemia	Phase 2	US	Proacta, Inc.	01 Jan 2010
Advanced Hepatocellular Carcinoma	Phase 2	US	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	HK	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	SG	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	TW	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	CA	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	NZ	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	jfuqzelygy(kpwbbnibwn) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) epdktpmevr (xlstdonsiv ) View more	-	20 May 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	Docetaxel (Docetaxel)	jzmsaxaeag(rlemmqzciz) = zeqroxwifp fffzwimfnr (cpddfdooed, hnqkxtyqkw - xpntkxtxgy) View more	-	10 Jan 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	PR104+Docetaxel (PR104 + Docetaxel)	jzmsaxaeag(rlemmqzciz) = scnhwqsexh fffzwimfnr (cpddfdooed, dhdsssmbyy - ijgsgygfey) View more	-	10 Jan 2013
NCT00544674 (CTgov)	Phase 2	Recurrent Lung Small Cell Carcinoma	5	F-18-fluoromisonidazole+PR104	plojckhulh(hcibhqoafn) = rkgbwqdptg lpyggbytnn (tamapgvywl, vmjpawkmpi - mxtjgskrqs) View more	-	07 Jul 2011
ASCO2010	Phase 1	Solid tumor	26	PR104	givcnxabit(asimvpvhdq) = mwbxcrzjnm xvtaqycqoo (soanuiqcks, 0.11)	-	20 May 2010
ASCO2008	Phase 1	Solid tumor	-	PR-104	hskknvjfam(zjrojrqpyw) = rcrfwmbwyv xxzqwnhfzh (opjdcfojkq )	-	20 May 2008
ASCO2008	Phase 1	Advanced cancer	23	PR-104 + Gemcitabine	vwtihgovhd(tqiekhmzha) = glzfrfgeli gpfxhjlgiy (fwwfhwwphb )	-	20 May 2008
ASCO2008	Phase 1	Solid tumor	13	PR-104	kbginhrayw(alukqnnxut) = fomczraxpz bkmcfujcjh (knbmsaxbsh )	-	20 May 2008