ChemicalBook Product Catalog Biochemical Engineering Inhibitors DNA damage PARP inhibitors PF-01367338

PF-01367338

Product NamePF-01367338
CAS459868-92-9
MFC19H21FN3O5P
MW421.37
EINECS
MOL File459868-92-9.mol

Chemical Properties

Melting point	>173°C (dec.)
storage temp.	Sealed in dry,Room Temperature
solubility	Soluble in DMSO (up to 25 mg/ml).
form	Yellow solid.
color	Yellow
Stability	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.

Usage And Synthesis

Description

Rucaparib phosphate (459868-92-9) is a potent (Ki<5 nM) PARP1 inhibitor.1Cytotoxic to human cancer cells or xenograft tumors with mutated or epigenetically silenced BRCA1/2.2Demonstrates antiproliferative effects in 26 out of 39 ovarian cancer cell lines.3Synergizes with other anticancer agents such as topotecan, carboplatin, doxorubicin, paclitaxel,3 and temozolomide.4Ameliorates the cardiotoxicity of doxorubicin.5Recently approved for human use by the FDA.

Uses

PARP inhibitor oncolytic

in vivo

Rucaparib (AG014699) phosphate and AG14584 significantly increase Temozolomide toxicity. Rucaparib (1 mg/kg) phosphate significantly increases Temozolomide-induced body weight loss. Rucaparib (0.1 mg/kg) phosphate results in a 50% increase in the temozolomide-induced tumor growth delay^[1].
Rucaparib (10 mg/kg for i.p. or 50, 150 mg/kg for p.o.; daily for 5 days per week for 6 weeks) phosphate significantly inhibits the growth of the tumor, and there is one complete tumor regression and two persistent partial regressions^[2].
Rucaparib (150 mg/kg; p.o.; once per week for 6 weeks or three times per week for 6 weeks) phosphate has greatest antitumor effect with three complete regressions^[2].
Rucaparib phosphate enhances the antitumor activity of temozolomide and indicates complete and sustained tumor regression in NB1691 and SHSY5Y xenografts^[6].

Animal Model:	Female athymic nude mice, implanted SW620 colorectal tumor cells (1 × 10⁷ cells per animal) s.c.^[1]
Dosage:	0.1 mg/kg in combination with Temozolomide (p.o., 200 mg/kg), 0.05, 0.15, and 0.5 mg/kg in combination with Temozolomide (p.o., 68 mg/kg) or 10 mg/kg
Administration:	IP, single dose for 0.1 mg/kg and 10 mg/kg, five daily doses for 0-0.5 mg/kg
Result:	Significantly increased Temozolomide toxicity, showed outstanding chemosensitization potency and caused enhancement of Temozolomide-induced tumor growth delay

Animal Model:	CD-1 nude mice bearing established Capan-1 xenografts^[2]
Dosage:	10 mg/kg or 50, 100 and 150mg/kg
Administration:	IP for 10 mg/kg; PO for 50, 100 and 150mg/kg, single dose (Pharmacokinetics)
Result:	Parent drug was detectable in the plasma only at 30min after 10mg/kg i.p and up to 4h for 50–150mg/kg p.o.. Was still detectable in most mice receiving oral rucaparib at 3 days. Does not easily cross the plasma membrane.

Animal Model:	CD-1 nude mice bearing established Capan-1 xenografts^[2]
Dosage:	10mg/kg i.p. daily for 5 days per week for 6 weeks, 50 or 150mg/kg p.o. daily × five weekly × six, 150mg/kg p.o. once per week for 6 weeks or three times per week for 6 weeks, or 150mg/kg p.o. daily for five days every 3 weeks
Administration:	IP or PO
Result:	10mg/kg i.p. significantly inhibited the growth of the tumor, daily oral administration at 150mg/kg had an equivalent effect on tumor growth to 10mg/kg i.p.. The schedule with the greatest antitumor effect was oral administration of 150mg/kg on a once weekly schedule with three complete regressions.

Animal Model:	CD-1 nude mice, NB1691 and SHSY5Y xenografts^[6]
Dosage:	1 mg/kg
Administration:	IP, daily for 5 d in combination with Temozolomide (orally daily ×5 at a dose of 68 mg/kg)
Result:	Enhanced the antitumor activity of Temozolomide and indicated complete and sustained tumor regression.

IC 50

PARP-1: 1.4 nM (Ki); PARP-2; PARP-3

References

[1] HUW D THOMAS. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.[J]. Molecular Cancer Therapeutics, 2007, 6 3: 945-956. DOI:10.1158/1535-7163.mct-06-0552
[2] YVETTE DREW. Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2.[J]. JNCI Journal of the National Cancer Institute, 2011, 103 4: 334-346. DOI:10.1093/jnci/djq509
[3] MAIKE IHNEN. Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.[J]. Molecular Cancer Therapeutics, 2013, 12 6: 1002-1015. DOI:10.1158/1535-7163.mct-12-0813
[4] RUTH PLUMMER. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.[J]. Cancer Chemotherapy and Pharmacology, 2013, 71 5: 1191-1199. DOI:10.1007/s00280-013-2113-1
[5] MAJID ALI. The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.[J]. Molecular Cancer Therapeutics, 2011, 10 12: 2320-2329. DOI:10.1158/1535-7163.mct-11-0356

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