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; phosphoric acid

• ChemBase ID: 72507
• Molecular Formular: C19H21FN3O5P
• Molecular Mass: 421.3593042
• Monoisotopic Mass: 421.12028564
• SMILES: c1(c2ccc(cc2)CNC)c2c3c([nH]1)cc(cc3C(=O)NCC2)F.P(=O)(O)(O)O
• Canonical SMILES: OP(=O)(O)O.CNCc1ccc(cc1)c1[nH]c2c3c1CCNC(=O)c3cc(c2)F
• InChI: 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)
• InChIKey: FCCGJTKEKXUBFZ-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• 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; phosphoric acid
• IUPAC Traditional 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; phosphoric acid
• Synonyms: AG-14447; AG-014447; AG-14699; PF-01367338; AG-014699

Database IDs

• CAS Number: 459868-92-9
• PubChem SID: 162037432
• PubChem CID: 9931953

CALCULATED PROPERTIES

• Acid pKa: 13.156606
• H Acceptors: 2
• H Donor: 3
• LogD (pH = 5.5): -0.7323592
• LogD (pH = 7.4): 0.28046802
• Log P: 2.45449
• Molar Refractivity: 92.9073 cm^3
• Polarizability: 37.137505 Å^3
• Polar Surface Area: 56.92 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: PARP

Product Information

• Salt Data: Phosphate

DETAILS

Selleck Chemicals - S1098

Research Area

• Description: Cancer

Biological Activity

• Description: Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with K_i of 1.4 nM.
• Targets: PARP
• IC50: 1.4 nM (K_i) ^[1]
• 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. ^[1] 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. ^[2] Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells. ^[3]
• 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. ^[3] 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. ^[4]
• Clinical Trials: Rucaparib is currently in Phase II clinical trials for locally advanced/metastatic breast or advanced ovarian cancer.
• Features: Rucaparib is the phosphate salt of AG-14447 and the first PARP inhibitor to be used in clinical trials, combined with temozolomide.

Protocol

• Protocol: 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. K_i is calculated by nonlinear regression analysis.
• Inhibition of PARP activity: Inhibition of PARP activity in 5 × 10^3 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 immunological detection of the amount of poly(ADP-ribose) (PAR) formed, using the 10H anti-PAR antibody, during a 6-min incubation with NAD^+ and oligonucleotide (substrate and activator). A PAR standard curve using a GCLP-validated assay is used as reference for the assay. ^[3]
• Protocol: Cell Assay ^[3]
• Cell Lines: D425Med, D283Med and D384Med cells
• Concentrations: 0.4 μM
• Incubation Time: 3 or 5 days
• Methods: Medulloblastoma cell lines are seeded in 96-well plates at a density of 1 × 10^3, 3 × 10^3 and 3 × 10^3, 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.
• Protocol: Animal Study ^[3]
• Animal Models: CD-1 nude mice bearing established D283Med xenografts
• Formulation: Normal saline
• Doses: 1 mg/kg
• Administration: One or four daily by i.p.

References

• References: [1] Thomas HD, et al. Mol Cancer Ther, 2007, 6(3), 945-956.
• References: [2] Hunter JE, et al. Oncogene, 2012, 31(2), 251-264.
• References: [3] Daniel RA, et al. Br J Cancer, 2010, 103(10), 1588-1596.
• References: [4] Daniel RA, et al. Clin Cancer Res, 2009, 15(4), 1241-1249.

REFERENCES

• Thomas HD, et al. Mol Cancer Ther, 2007, 6(3), 945-956.
• Hunter JE, et al. Oncogene, 2012, 31(2), 251-264.
• Daniel RA, et al. Br J Cancer, 2010, 103(10), 1588-1596.
• Daniel RA, et al. Clin Cancer Res, 2009, 15(4), 1241-1249.