Rucaparib (AG-014699,PF-01367338)

Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with Ki of 1.4 nM for PARP1, also showing binding affinity to eight other PARP domains. Phase 3.

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Rucaparib (AG-014699,PF-01367338) Chemical Structure

Rucaparib (AG-014699,PF-01367338) Chemical Structure
Molecular Weight: 421.36

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

Related Compound Libraries

Rucaparib (AG-014699,PF-01367338) is available in the following compound libraries:

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Product Information

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  • Research Area

Product Description

Biological Activity

Description Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with Ki of 1.4 nM for PARP1, also showing binding affinity to eight other PARP domains. Phase 3.
Targets PARP [1]
IC50 1.4 nM(Ki)
In vitro Rucaparib is a potent inhibitor of purified full-length human PARP-1 and shows higher inhibition of cellular PARP in LoVo and SW620 cells. Besides, Rucaparib binds detectably to eight other PARP domains, including PARP2, 3, 4, 10, 15, 16, TNKS1 and TNKS2. [1] [2] The radio-sensitization by Rucaparib is due to downstream inhibition of activation of NF-κB, and is independent of SSB repair inhibition. Rucaparib could target NF-κB activated by DNA damage and overcome toxicity observed with classical NF-κB inhibitors without compromising other vital inflammatory functions. [3] Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells. [4]
In vivo Rucaparib is not toxic but significantly enhances temozolomide-induced TGD in the DNA repair protein-competent D384Med xenografts. Pharmacokinetics studies also show that Rucaparib is detected in the brain tissue, which indicates that Rucaparib has potential in intra-cranial malignancy therapy. [4] Rucaparib significantly potentiates the cytotoxicity of topotecan and temozolomide in NB-1691, SH-SY-5Y, and SKNBE (2c) cells. Rucaparib enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts. [5]
Features The first PARP inhibitor used in clinical trials combined with temozolomide.

Protocol(Only for Reference)

Kinase Assay: [1]

Ki Determination Inhibition of human full-length recombinant PARP-1 by [32P]NAD+ incorporation is measured. The [32P]ADP-ribose incorporated into acid insoluble material is quantified using a PhosphorImager. Ki is calculated by nonlinear regression analysis.
Inhibition of PARP activity Inhibition of PARP activity in 5 × 103 D283Med cells is measured using various concentrations of Rucaparib (0-1 μM), compared with DMSO-only. Maximally stimulated PARP activity is measured in samples of permeabilised cells by immunologica

Cell Assay: [4]

Cell lines D425Med, D283Med and D384Med cells
Concentrations 0.4 μM
Incubation Time 3 or 5 days
Method Medulloblastoma cell lines are seeded in 96-well plates at a density of 1 × 103, 3 × 103 and 3 × 103, respectively. At 24 hours (D384Med) or 48 hours (D283Med and D425Med) after seeding, the cells are exposed to various concentrations of temozolomide in the presence or absence of 0.4 μM Rucaparib. After 3 days (D425Med and D384Med) or 5 days (D283Med) of culture, cell viability is evaluated by a XTT cell proliferation kit assay. Cell growth is expressed as a percentage in relation to DMSO or 0.4 μM Rucaparib-alone controls. The concentration of temozolomide, alone or in combination with Rucaparib that inhibited growth by 50% (GI50) is calculated. The potentiation factor 50 (PF50) is defined as the ratio of the GI50 of temozolomide in the presence of Rucaparib to the GI50 of temozolomide alone.

Animal Study: [4]

Animal Models CD-1 nude mice bearing established D283Med xenografts
Formulation Normal saline
Dosages 1 mg/kg
Administration One or four daily by i.p.
Solubility 30% propylene glycol, 5% Tween 80, 65% D5W, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Thomas HD, et al. Mol Cancer Ther, 2007, 6(3), 945-956.

[2] Kotz, J. SciBX 5(13); doi:10.1038/scibx.2012.323.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02042378 Recruiting Pancreatic Cancer|Pancreatic Ductal Adenocarcinoma Clovis Oncology, Inc. April 2014 Phase 2
NCT01968213 Recruiting Ovarian Cancer|Fallopian Tube Cancer|Peritoneal Cancer Clovis Oncology, Inc. January 2014 Phase 3
NCT01891344 Recruiting Ovarian Cancer|Epithelial Ovarian Cancer|Fallopian Tube Cancer|Peritoneal Cancer Clovis Oncology, Inc. September 2013 Phase 2
NCT01482715 Recruiting Ovarian Cancer|Fallopian Tube Cancer|Peritoneal Cancer Clovis Oncology, Inc. November 2011 Phase 1|Phase 2
NCT01009190 Active, not recruiting Advanced Solid Tumors Clovis Oncology, Inc. February 2010 Phase 1

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Chemical Information

Download Rucaparib (AG-014699,PF-01367338) SDF
Molecular Weight (MW) 421.36
Formula

C19H18FN3O.H3PO4

CAS No. 459868-92-9
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 84 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 8-fluoro-5-(4-((methylamino)methyl)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one phosphoric acid

Research Area

Customer Reviews (2)


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Rating
Source Dr. David Schürmann from University of Base. Rucaparib (AG-014699,PF-01367338) purchased from Selleck
Method Kruskal-Wallis and the post-hoc Dunn’s Multiple Comparison tests, immuno-staining
Cell Lines Primary human lung fibroblast cells (MRC-5)
Concentrations 0-1 μM
Incubation Time 2 h
Results

Click to enlarge
Rating
Source J Biol Chem, 2012, 287(47), 39824-33. Rucaparib (AG-014699,PF-01367338) purchased from Selleck
Method Western Blotting
Cell Lines HaCaT cells
Concentrations 1 μM
Incubation Time 30 min
Results preincubation of purified PARP-1 with AG-014699, a potent PARP inhibitor , prior to PARP-1 activation led to decreased associa-tion between PARP-1 and XPA.

Product Citations (15)

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