RUCAPARIB PHOSPHATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H18FN3O.H3O4P
Molecular Weight	421.3593
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(O)=O.CNCC1=CC=C(C=C1)C2=C3CCNC(=O)C4=CC(F)=CC(N2)=C34

InChI

InChIKey=FCCGJTKEKXUBFZ-UHFFFAOYSA-N

InChI=1S/C19H18FN3O.H3O4P/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;1-5(2,3)4/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24);(H3,1,2,3,4)

HIDE SMILES / InChI

Description
Sources: https://www.drugs.com/history/rubraca.html

Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of advanced mutant BRCA ovarian cancer. Rucaparib is being investigated in clinical trials against prostate cancer, breast cancer and other neoplasms.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
PARP 1, 2 and 3 9 Target ID: CHEMBL3390820 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf	Inhibitor 8297		0.804 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 157 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf	Primary	Approved 8429	RUBRACA Approved Use RUBRACA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy 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. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. Launch Date 2016
Breast cancer 434 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27002934	Primary	Phase II 1132	Unknown Approved Use Unknown
Castrate-resistant prostate cancer 20 Sources: https://clinicaltrials.gov/ct2/show/NCT02952534	Primary	Phase III 656	Unknown Approved Use Unknown
Melanoma 88 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23423489	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
629 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29799676	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		RUCAPARIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
5740 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29799676	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		RUCAPARIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
15.2 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29799676	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		RUCAPARIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
840 mg 2 times / day steady, oral Highest studied dose Dose: 840 mg, 2 times / day Route: oral Route: steady Dose: 840 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28264872	unhealthy, 51 years (range: 21–71 years) n = 3 Health Status: unhealthy Age Group: 51 years (range: 21–71 years) Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/28264872	Other AEs: Asthenia, Fatigue... Other AEs: Asthenia (33.3%) Fatigue (33.3%) Nausea (100%) Vomiting (66.7%) Diarrhea (100%) Decreased appetite (33.3%) Alanine aminotransferase increase (33.3%) Transaminases increased (33.3%) Headache (33.3%) Abdominal pain (33.3%) Dysgeusia (14.3%) Dyspnea (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/28264872
18 mg/m2 1 times / day multiple, intravenous Dose: 18 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 18 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27002934	unhealthy, 52 years (range: 23–72 years) n = 33 Health Status: unhealthy Age Group: 52 years (range: 23–72 years) Sex: F Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/27002934	Sources: https://pubmed.ncbi.nlm.nih.gov/27002934
600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf	unhealthy, 62 years (range: 31 - 86 years) n = 377 Health Status: unhealthy Condition: ovarian cancer Age Group: 62 years (range: 31 - 86 years) Sex: F Population Size: 377 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf	Disc. AE: Fatigue, Asthenia... AEs leading to discontinuation/dose reduction: Fatigue (2%) Asthenia (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf
600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-77	unhealthy, 62 years (range: 31 - 86 years) n = 378 Health Status: unhealthy Condition: ovarian cancer Age Group: 62 years (range: 31 - 86 years) Sex: F Population Size: 378 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-77	Disc. AE: Intestinal obstruction, Small intestinal obstruction... AEs leading to discontinuation/dose reduction: Intestinal obstruction (1.7%) Small intestinal obstruction (1.7%) Nausea (1.3%) Abdominal pain (1.1%) Abdominal pain upper (1.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-77
600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-81	unhealthy, 62 years (range: 31 - 86 years) n = 378 Health Status: unhealthy Condition: ovarian cancer Age Group: 62 years (range: 31 - 86 years) Sex: F Population Size: 378 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-81	Disc. AE: Anemia, Fatigue... AEs leading to discontinuation/dose reduction: Anemia (21.2%) Fatigue (19.8%) Asthenia (19.8%) Hemoglobin decreased (21.2%) Nausea (17.2%) Vomiting (11.4%) Alanine aminotransferase increased (9.8%) Thrombocytopenia (9.8%) Platelet count decreased (6.6%) Neutrophil count decreased (6.3%) Neutropenia (6.3%) Blood creatinine increased (5%) Abdominal pain (4.7%) Abdominal pain upper (4.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: p. 11-81
600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32128485	unhealthy, 86 years n = 1 Health Status: unhealthy Age Group: 86 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/32128485	Disc. AE: Torsades de pointes... AEs leading to discontinuation/dose reduction: Torsades de pointes (grade 5, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/32128485

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737 supressor 21	inhibitor 1767 substrate 1037	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 BCRP 699 OCT1 512 OCT2 647 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 MATE2 263 BSEP 402 CYP1A2 1524 CYP2B6 810 CYP2C19 1478 CYP2C8 911 MATE1 306 MRP2 383 MRP3 157 MRP4 204 UGT1A1 204	BCRP 561 CYP1A2 1054 CYP2C19 991 OAT1 326 OAT3 339 OATP1B1 406 OATP1B3 350 OCT2 355 P-gp 1537	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
OAT1 603	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	no [Inhibition 300 uM]
OAT3 644	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	no [Inhibition 300 uM]
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	no [Inhibition 300 uM]
OATP1B3 715	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	no [Inhibition 300 uM]
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
MRP3 207	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
MATE2 263	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/\|https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf	strong [IC50 0.19 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf\|https://pubmed.ncbi.nlm.nih.gov/32129697/ Page: 57.0	strong [IC50 0.63 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0	yes [IC50 12.9 uM]	yes (co-administration study) Comment: warfarin AUC increased 1.49-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/\|https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf	yes [IC50 169 uM]	weak (co-administration study) Comment: digoxin AUC increased 1.2-fold Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/\|https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0	yes [IC50 3.55 uM]	yes (co-administration study) Comment: caffeine AUC increased 2.55-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0
OCT2 648	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	yes [IC50 31 uM]
OCT1 543	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	yes [IC50 4.3 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	yes [IC50 41.6 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0	yes [IC50 5.42 uM]	yes (co-administration study) Comment: omeprazole AUC increased 1.55-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32129697/	yes [IC50 55 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
CYP2B6 1001	supressor 155 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
CYP3A4 1925	supressor 155 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
MRP4 238	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0	yes	yes (co-administration study) Comment: midazolam AUC increased 1.38-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 14.0

Drug as victim

Target	Modality	Activity	Clinical evidence
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: 56, 59, 65	no	no (pharmacogenomic study) Comment: based on population PK analyses there appeared to be no significant difference in steady-state exposure of rucaparib among CYP2D6 phenotypes Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: 56, 59, 65
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 15.0	yes
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 1.0	yes
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 1.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 1.0	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: 57.0	yes
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 1.0	yes	no (pharmacogenomic study) Comment: based on population PK analyses there appeared to be no significant difference in steady-state exposure of rucaparib among CYP1A2 phenotypes Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s008lbl.pdf Page: 1.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf Page: 38.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:134689	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:134689
ChemicalBook	CB51475507	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB51475507
MolPort	MolPort-028-744-762	https://www.molport.com/shop/molecule-link/MolPort-028-744-762
ZINC	ZINC000000025958	http://zinc15.docking.org/substances/ZINC000000025958

PubMed

Title	Date	PubMed
Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines.	2000 Jul	10914735
Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361.	2004 Jan 7	14709739
Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.	2007 Mar	17363489

Patents

Sample Use Guides

In Vivo Use Guide

Recommended dose is 600 mg orally twice daily with or without food.

Route of Administration: Oral

In Vitro Use Guide

Exponentially proliferating cells were plated into six-well plates and incubated for 48 hours to allow cells to reach their optimum proliferation rate. AG014699 at 0, 0.1, 1.0, 10.0, 30.0, 50.0, or 100 μM in 1% dimethyl sulfoxide was added to the wells and incubated for 24 hours. Control cells received no AG014699 but were treated with medium containing 1% dimethyl sulfoxide for 24 hours. Cells were harvested and cultured in drug-free medium in 90-mm Petri dishes for up to 21 days, depending on the proliferation rate of the individual cell line. Colonies were fixed in methanol and acetic acid (3:1 vol/vol), stained with methyl violet 10B, and counted with an automated colony counter (Oxford Optronix, Oxford, UK). Data are expressed as the percentage of colonies in AG014699-treated cultures compared with that in control cultures. AG014699 (≤10 μM) was cytotoxic to cells with mutated BRCA1/2 or XRCC3 and to UACC3199 cells with epigenetically silenced BRCA1 but not to cells without BRCA1/2 or XRCC3 mutations or that were heterozygous for BRCA2 mutation

Name

Type

Language

RUCAPARIB PHOSPHATE

Official Name

English

8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one phosphate (1:1)

Systematic Name

English

PF-01367338

Code

English

6H-AZEPINO(5,4,3-CD)INDOL-6-ONE, 8-FLUORO-1,3,4,5-TETRAHYDRO-2-(4((METHYLAMINO)METHYL)PHENYL)-, PHOSPHATE (1:1)

Systematic Name

English

Rucaparib phosphate [WHO-DD]

Common Name

English

6H-PYRROLO(4,3,2-EF)(2)BENZAZEPIN-6-ONE, 8-FLUORO-1,3,4,5-TETRAHYDRO-2-(4-((METHYLAMINO)METHYL)PHENYL)-, PHOSPHATE (1:1)

Systematic Name

English

AG-014699

Code

English

AG014699

Code

English

AG-14699

Code

English

RUCAPARIB PHOSPHATE [USAN]

Common Name

English

PF01367338

Code

English

AG 014699

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C62554