Identification
NameRucaparib
Accession NumberDB12332
TypeSmall Molecule
GroupsApproved, Investigational
Description

Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved (accelerated ) in December 2016 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.

Structure
Thumb
SynonymsNot Available
External IDs AG-14447
Product Ingredients
IngredientUNIICASInChI KeyDetails
Rucaparib camsylate41AX9SJ8KO 1859053-21-6INBJJAFXHQQSRW-STOWLHSFSA-NDetails
Rucaparib phosphateH3M9955244 459868-92-9FCCGJTKEKXUBFZ-UHFFFAOYSA-NDetails
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RubracaTablet, film coated200 mg/1OralClovis Oncology, Inc.2016-12-19Not applicableUs
RubracaTablet, film coated300 mg/1OralClovis Oncology, Inc.2016-12-19Not applicableUs
RubracaTablet, film coated250 mg/1OralClovis Oncology, Inc.2017-05-01Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII8237F3U7EH
CAS number283173-50-2
WeightAverage: 323.371
Monoisotopic: 323.143390375
Chemical FormulaC19H18FN3O
InChI KeyHMABYWSNWIZPAG-UHFFFAOYSA-N
InChI
InChI=1S/C19H18FN3O/c1-21-10-11-2-4-12(5-3-11)18-14-6-7-22-19(24)15-8-13(20)9-16(23-18)17(14)15/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24)
IUPAC Name
6-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,10-diazatricyclo[6.4.1.0^{4,13}]trideca-1,4,6,8(13)-tetraen-9-one
SMILES
CNCC1=CC=C(C=C1)C1=C2CCNC(=O)C3=C2C(N1)=CC(F)=C3
Pharmacology
Indication

treatment of ovarian cancer, specifically those with alterations in BRCA1 and BRCA2 genes in the tumor tissue of ovarian cancer.

Structured Indications Not Available
Pharmacodynamics

Cardiac Electrophysiology: The effect of multiple doses of rucaparib on QTc interval was evaluated in an open-label single-arm study in 56 patients with solid tumors who were administered continuous doses of rucaparib ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean QTcF increase from baseline (90% confidence interval [CI]) in population pharmacokinetics estimated 95% percentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib twice daily was 14.9 msec (11.1-18.7 msec)

Mechanism of action

Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased rucaparib-induced cytotoxicity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA. Rucaparib sensitise cancer cells to X-radiation or (131)I-meta-iodobenzylguanidine treatment. It is likely that the mechanism of radiosensitisation entails the accumulation of unrepaired radiation-induced DNA damage. The administration of PARP-1 inhibitors and (131)I-meta-iodobenzylguanidine to high risk neuroblastoma patients would be beneficial

TargetKindPharmacological actionActionsOrganismUniProt ID
Poly [ADP-ribose] polymerase 1Proteinyes
antagonist
HumanP09874 details
Poly [ADP-ribose] polymerase 2Proteinyes
antagonist
HumanQ9UGN5 details
Poly [ADP-ribose] polymerase 3Proteinyes
antagonist
HumanQ9Y6F1 details
Related Articles
Absorption

The median T max was 1.9 hours at the approved recommended dosage. The mean absolute bioavailability of rucaparib immediate-release tablet was 36% with a range from 30% to 45%. Following a high-fat meal, the Cmax was increased by 20% and AUC 0-24h was increased by 38%, and T max was delayed by 2.5 hours, as compared to dosing under fasted conditions

Volume of distribution

Rucaparib had a steady-state volume of distribution of 113 L to 262 L following a single intravenous dose of 12 mg to 40 mg rucaparib.

Protein binding

70%

Metabolism

In vitro, rucaparib was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.

Route of elimination

Fecal excretion was the major route of elimination, accounting for ≥ 79% of the total dose.

Half life

The mean terminal T 1/2 of rucaparib was 17 to 19 hours, following a single oral dose of 600 mg rucaparib.

Clearance

The apparent clearance ranged from 15.3 to 79.2 L/hour, following continuous 600 mg rucaparib orally twice daily. The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg.

Toxicity

Not Available

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Rucaparib.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Rucaparib.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Rucaparib.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Rucaparib.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Rucaparib.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Rucaparib.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Rucaparib.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Rucaparib.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Rucaparib.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Rucaparib.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Rucaparib.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Rucaparib.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Nile DL, Rae C, Hyndman IJ, Gaze MN, Mairs RJ: An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma. BMC Cancer. 2016 Aug 11;16:621. doi: 10.1186/s12885-016-2656-8. [PubMed:27515310 ]
  2. Jenner ZB, Sood AK, Coleman RL: Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol. 2016 Jun;12(12):1439-56. doi: 10.2217/fon-2016-0002. Epub 2016 Apr 18. [PubMed:27087632 ]
  3. Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer R: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer. 2016 Mar 29;114(7):723-30. doi: 10.1038/bjc.2016.41. Epub 2016 Mar 22. [PubMed:27002934 ]
  4. CENTER FOR DRUG EVALUATION AND RESEARCH [Link]
  5. Daily med. [Link]
  6. FDA Label [Link]
  7. wikipedia [Link]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherNeoplasms1
1CompletedTreatmentAdvanced Solid Tumors1
1RecruitingOtherTumors, Solid1
1RecruitingTreatmentNeoplasms, Gynecologic1
1, 2Active Not RecruitingTreatmentAdvanced Solid Tumor With Evidence of Germline or Somatic BRCA / Cancer, Ovarian / Fallopian Tube Cancer / Peritoneal Cancer1
2Active Not RecruitingTreatmentCancer, Breast1
2Active Not RecruitingTreatmentCancer, Ovarian / Fallopian Tube Cancer / Ovarian Epithelial Cancer / Peritoneal Cancer1
2CompletedTreatmentBRCA1 Mutation Carrier / BRCA2 Mutation Carrier / Cancer, Breast / Cancer, Ovarian1
2CompletedTreatmentMalignant Neoplasm of Pancreas / Pancreatic Ductal Adenocarcinoma1
2RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer1
2WithdrawnTreatmentDiabetes Mellitus (DM) / Retinopathy, Diabetic1
3Active Not RecruitingTreatmentCancer, Ovarian / Fallopian Tube Cancer / Peritoneal Cancer1
3RecruitingTreatmentCancer, Ovarian / Fallopian Tube Cancer / Ovarian Epithelial Cancer / Peritoneal Cancer1
3RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral250 mg/1
Tablet, film coatedOral300 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8859562 No2011-08-042031-08-04Us
US8143241 No2007-08-122027-08-12Us
US6495541 No2000-01-102020-01-10Us
US8754072 No2011-02-102031-02-10Us
US9045487 No2011-02-102031-02-10Us
US8071579 No2007-08-122027-08-12Us
US7531530 No2004-07-232024-07-23Us
US7351701 No2004-07-232024-07-23Us
Properties
StateNot Available
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0114 mg/mLALOGPS
logP2.39ALOGPS
logP2.45ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)13.16ChemAxon
pKa (Strongest Basic)9.32ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area56.92 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity92.91 m3·mol-1ChemAxon
Polarizability35.19 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET featuresNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 2-phenylindoles. These are indoles substituted at the 2-position with a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassIndoles
Direct Parent2-phenylindoles
Alternative ParentsPhenylpyrroles / Benzazepines / 3-alkylindoles / Phenylmethylamines / Benzylamines / Aralkylamines / Azepines / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides
Substituents2-phenylindole / Benzazepine / 2-phenylpyrrole / 3-alkylindole / Benzylamine / Phenylmethylamine / Aralkylamine / Azepine / Benzenoid / Aryl fluoride
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Zinc ion binding
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR...
Gene Name:
PARP1
Uniprot ID:
P09874
Uniprot Name:
Poly [ADP-ribose] polymerase 1
Molecular Weight:
113082.945 Da
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Nad+ adp-ribosyltransferase activity
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks.
Gene Name:
PARP2
Uniprot ID:
Q9UGN5
Uniprot Name:
Poly [ADP-ribose] polymerase 2
Molecular Weight:
66205.31 Da
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Nad+ adp-ribosyltransferase activity
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. May link the DNA damage surveillance network to the ...
Gene Name:
PARP3
Uniprot ID:
Q9Y6F1
Uniprot Name:
Poly [ADP-ribose] polymerase 3
Molecular Weight:
60069.7 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Uniprot Name:
Cytochrome P450 2D6
Molecular Weight:
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Uniprot Name:
Cytochrome P450 1A2
Molecular Weight:
58293.76 Da
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Uniprot Name:
Cytochrome P450 3A4
Molecular Weight:
57342.67 Da
Drug created on October 20, 2016 15:59 / Updated on September 01, 2017 12:19