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Rucaparib (formerly known as AG-14447; AG-014699; PF-01367338; Rubraca) is an inhibitor of PARP [ (poly(ADP-Ribose) polymerase)] with anticancer effects. In a cell-free assay, it inhibits PARP1 with a Ki of 1.4 nM. The FDA approved rucaparib in 2016 for the treatment of ovarian cancer in female patients. Rucaparib binds specifically to PARP1 and prevents PARP1 from repairing damaged DNA, which increases the number of breaks in DNA strands and encourages apoptosis and genomic instability. This could reverse tumor cell resistance to chemotherapy and radiation therapy and increase the cytotoxicity of agents that damage DNA.
Physicochemical Properties
| Molecular Formula | C19H18FN3O |
| Molecular Weight | 323.37 |
| Exact Mass | 323.143 |
| Elemental Analysis | C, 70.57; H, 5.61; F, 5.88; N, 12.99; O, 4.95 |
| CAS # | 283173-50-2 |
| Related CAS # | 1859053-21-6 (camsylate); 459868-92-9 (phosphate); 283173-50-2 |
| PubChem CID | 9931954 |
| Appearance | Yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 625.2±55.0 °C at 760 mmHg |
| Flash Point | 331.9±31.5 °C |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C |
| Index of Refraction | 1.649 |
| LogP | 2.85 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 24 |
| Complexity | 466 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC1=C([H])C2C(N([H])C([H])([H])C([H])([H])C3=C(C4C([H])=C([H])C(C([H])([H])N([H])C([H])([H])[H])=C([H])C=4[H])N([H])C(=C1[H])C3=2)=O |
| InChi Key | HMABYWSNWIZPAG-UHFFFAOYSA-N |
| InChi Code | 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) |
| Chemical Name | 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one |
| Synonyms | AG014699; PF-01367338; AG 14447; AG 014699; PF 01367338; AG-014699,PF01367338; AG-14447; AG14447; Trade name: Rubraca |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | PARP-1 ( Ki = 1.4 nM ); PARP-2; PARP-3 | ||
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | The amount of [32P]NAD+ incorporation-induced inhibition of human full-length recombinant PARP-1 is measured. With a PhosphorImager, the amount of [32P]ADP-ribose added to acid-insoluble material is measured. The nonlinear regression analysis is used to calculate Ki. | ||
| Cell Assay | The MTT assay is used to measure cell proliferation. In 96-well plates, the cells are seeded at a density of 5×103 cells/ml in a volume of 200 μl/well. The following day, DMSO, BKM120, or rucaparib are added in varying concentrations to the cells. Each well receives 20 μl of MTT (5 mg/ml) after four days. Following an additional 4-hour incubation period at 37 °C, the absorbance at 490 nm is determined. CalcuSyn software is used to analyze data from growth inhibitory experiments in order to ascertain the effect of drug combinations. Next, combination indexes (CI) are computed. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rucaparib exhibits a linear pharmacokinetic profile over the dose range from 240 mg to 840 mg twice daily. The mean (coefficient of variation [CV]) steady-state rucaparib Cmax is 1940 ng/mL (54%) and AUC0-12h is 16900 h x ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold. The median Tmax at the steady state is 1.9 hours, with a range of 0 to 5.98 hours at the approved recommended dosage. The mean absolute bioavailability is 36%, with a range of 30 to 45%. A high-fat meal increased Cmax and AUC0-24h by 20% and 38%, respectively. The Tmax was delayed by 2.5 hours. Following a single oral dose of radiolabeled rucaparib, unchanged rucaparib accounted for 64% of the radioactivity. Rucaparib accounted for 45% and 95% of radioactivity in urine and feces, respectively. The mean (coefficient of variation) apparent volume of distribution is 2300 L (21%). The mean (coefficient of variation) apparent total clearance at steady state is 44.2 L/h (45%). Metabolism / Metabolites In vitro, rucaparib is primarily metabolized by CYP2D6 and, to a lesser extent, by CYP1A2 and CYP3A4. In addition to CYP-based oxidation, rucaparib also undergoes N-demethylation, N-methylation, and glucuronidation. In one study, seven metabolites of rucaparib were identified in plasma, urine, and feces. Biological Half-Life The mean (coefficient of variation) terminal elimination half-life is 26 (39%) hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity In large clinical trials of rucaparib, abnormalities in routine liver tests were common; serum ALT elevations arising in 74% with values above 5 times the upper limit of normal (ULN) in 13%. Despite the frequency of serum enzyme elevations during therapy in clinical trials, there were no reports of hepatitis with jaundice or liver failure. Subsequent to its approval and more wide scale use, there have been no published reports of clinically apparent liver injury attributed to rucaparib. Thus, rucaparib is a frequent cause of serum enzyme elevations, but has not been linked to significant hepatotoxicity. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of rucaparib during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during rucaparib therapy and for 2 weeks after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Rucaparib is 70% bound to human plasma proteins _in vitro_. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.8. |
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| References |
[1]. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol Cancer Ther, 2007, 6(3), 945-956. [2]. Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules. Br J Cancer. 2014 Apr 15;110(8):1977-84. [3]. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res, 2009, 15(4), 1241-1249. [4]. Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation. Sci Transl Med. 2021 May 26;13(595):eabe8226. [5]. NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699. Oncogene, 2012, 31(2), 251-264. [6]. Rucaparib: A Review in Ovarian Cancer. Target Oncol. 2019 Apr;14(2):237-246. |
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| Additional Infomation |
Pharmacodynamics Rucaparib is an anticancer agent that exerts cytotoxic effects against cancer cells. It works by inhibiting poly (ADP-ribose) polymerase (PARP), an enzyme that plays a role in DNA repair. Rucaparib inhibits PARP-1, PARP-2, and PARP-3. It also interacts with PARP-4, PARP-10, PARP-12, PARP-15, and PARP-16, but to a lesser extent. In mice, rucaparib accumulated and was retained in tumours, inhibiting PARP enzymes for seven days. Rucaparib decreases tumour growth in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. In addition to PARP inhibition, rucaparib demonstrated PARP-independent cytotoxic mechanisms in cancer cells. When co-administered with other chemotherapeutic agents, rucaparib contributed to synergistic or additive effects _in vitro_ and _in vivo_. There is evidence that rucaparib can sensitize cancer cells to chemotherapy. Rucaparib can also cause vasodilation, which may increase tumour perfusion and enhance the accumulation of cytotoxic drugs in cancer cells. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.73 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (7.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0924 mL | 15.4622 mL | 30.9243 mL | |
| 5 mM | 0.6185 mL | 3.0924 mL | 6.1849 mL | |
| 10 mM | 0.3092 mL | 1.5462 mL | 3.0924 mL |