Rucaparib (AG-014699,PF-01367338)

Rucaparib (AG-014699, PF-01367338)は一種のPARP阻害剤で、無細胞試験でPARP1に作用する時のKi値が1.4 nMになって、残り8つPARPドメインにも結合親和力を表します。臨床3期。

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Rucaparib (AG-014699,PF-01367338) 化学構造
分子量: 421.36

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製品説明

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製品の説明

生物活性

製品説明 Rucaparib (AG-014699, PF-01367338)は一種のPARP阻害剤で、無細胞試験でPARP1に作用する時のKi値が1.4 nMになって、残り8つPARPドメインにも結合親和力を表します。臨床3期。
ターゲット PARP
IC50 1.4 nM (Ki) [1]
In vitro試験 Rucaparib is a potent inhibitor of purified full-length human PARP-1 and shows higher inhibition of cellular PARP in LoVo and SW620 cells. Besides, Rucaparib binds detectably to eight other PARP domains, including PARP2, 3, 4, 10, 15, 16, TNKS1 and TNKS2. [1] [2] 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. [3] Rucaparib inhibits PARP-1 activity by 97.1% at a concentration of 1 μM in permeabilised D283Med cells. [4]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
BT-474 MWfGeY5kfGmxbjDBd5NigQ>? M2nYWVAvOS9zL{WwNE8yODByIH7N M2fwXIlvcGmkaYTzJHBCWlBiYXP0bZZqfHliYYSgd5RienSrbnegZ49v[2W{boTyZZRqd25ib3[gOVAxKG6P MX[yOVEzQDR3NR?=
BT474 NWHXRXM{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4DmOlUxOCCwTR?= NIKzOJUyOOLCk{G1xsBl MljFdoVlfWOnczDj[YxtKGe{b4f0bEBqdiC2aHWg[o92eiCuaX7ld{BidmRic3nncolncWOjboTsfS=> MWKyOVEzQDR3NR?=
SKBR3 NV3kVW5vT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{j1VVUxOCCwTR?= Mk\INVDjiJNzNdMg[C=> MYPy[YR2[2W|IHPlcIwh\3Kxd4ToJIlvKHSqZTDmc5VzKGyrbnXzJIFv\CC|aXfubYZq[2GwdHz5 MnvnNlUyOjh2NUW=
AU565 M321fGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYHCOVBqPTByIH7N MkLoNVDjiJNzNdMg[C=> NVe5e|NmemWmdXPld{Bk\WyuIHfyc5d1cCCrbjD0bIUh\m:3cjDsbY5meyCjbnSgd4lodmmoaXPhcpRtgQ>? NF;yc5AzPTF{OES1OS=>
EFM192A Ml7lS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEXnXZE2ODBibl2= M2P1OlEx6oDVMUZCpIQ> NHT5WmRz\WS3Y3XzJINmdGxiZ4Lve5RpKGmwIITo[UBnd3W{IHzpcoV{KGGwZDDzbYdvcW[rY3HueIx6 MmTTNlUyOjh2NUW=
MDA-MB-231 M36zXWZ2dmO2aX;uJGF{e2G7 M1zmXFExNzJyL{SwJO69VQ>? M2HreVI1KGh? MmDFbY5kemWjc3XzJJAuSUuWIHzleoVteyCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>? M2TJUVI1PDJyMUWy
MDA-MB-231 M4rkVmNmdGxiVnnhZoltcXS7IFHzd4F6 MUOwMlEuPDBizszN NFPxWVUzPCCq M2GwUGlEPTEkgJm95qCKOTdwN{hCpO69VQ>? NYfJfGdCOjR2MkCxOVI>
MDA-MB-231 MYLBdI9xfG:|aYOgRZN{[Xl? Ml;QNVAwOjBxNECg{txO M37UUVI1KGh? M2fqbYlv\HWlZYOgZZBweHSxc3nzJIRwe2ViZHXw[Y5l\W62bIm= M3v3XlI1PDJyMUWy
MDA-MB-231 M3HSXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFvzOVMyOC9{MD:0NEDPxE1? NVSxdVJZOjRiaB?= M1nndIJtd2OtczDj[YxtKGO7Y3zlJJBzd2e{ZYPzbY9vKGmwIFeyM20heGijc3W= NFHkNYwzPDR{MEG1Ni=>
H460 MnHwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUPad4t3PDByIH7N NFrkS3EzPMLiaB?= NGqxSYtqdmO{ZXHz[ZMh[2WubIXsZZIhemGmaX;z[Y5{cXSrdnn0fS=> NYnFfXR2OjR2MUG2NVE>
A549  NHPVeZFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHrlfYg1ODBibl2= MXmyOOKhcA>? NYrIXmRbcW6lcnXhd4V{KGOnbHz1cIFzKHKjZHnvd4Vve2m2aY\peJk> NV7wbnVFOjR2MUG2NVE>
DT40 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYXJR|UxRTJzIH7N M2\3S|I1OzV4OEGz
DU145 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MX7JR|UxRTF6IH7N NInufJUzPDN3NkixNy=>
COLO704 MmC1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHPRfXBKSzVyPUKuOVIhyrFiMD62O{DPxE1? M{PkTlI{PzJ7NECy
OVMANAb NYXafXJsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWrJR|UxRTJwNUigxtEhOC5|ODFOwG0> MUGyN|czQTRyMh?=
OV177 M3rnXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4DpSmlEPTB;Mj63PEDDuSByLkexJO69VQ>? NWKzdldVOjN5Mkm0NFI>
OAW28 MoLiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnPmTWM2OD1|Lk[xJOKyKDBwMkig{txO MXSyN|czQTRyMh?=
OVSAHO M4\3R2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlvxTWM2OD1|Lk[0JOKyKDBwM{Og{txO MWKyN|czQTRyMh?=
OVKATE MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXzJR|UxRTNwNkSgxtEhOS55OTFOwG0> MYOyN|czQTRyMh?=
OVCAR3 MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWXJR|UxRTNwN{SgxtEhOC52MDFOwG0> NFKwc2EzOzd{OUSwNi=>
PEO14 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mlq2TWM2OD1|Lki0JOKyKDBwN{[g{txO MoDpNlM4Ojl2MEK=
A2780 NHLEeJlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEXacIFKSzVyPUOuPVQhyrFiMD6yOUDPxE1? M{C3eFI{PzJ7NECy
OVTOKO MonYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1;RdWlEPTB;ND6xOEDDuSBzLkWzJO69VQ>? NVnxUGZVOjN5Mkm0NFI>
KURAMOCHIb MoTVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mmr6TWM2OD12LkO0JOKyKDBwMkmg{txO MUeyN|czQTRyMh?=
TOV21G M33IeWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUnJR|UxRTVwMEegxtEhOS5|MDFOwG0> Mm\oNlM4Ojl2MEK=
OVISE NFq1XmVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXLlemFbUUN3ME21MlY5KMLzIECuNlMh|ryP NUXlfWdiOjN5Mkm0NFI>
KK M1u3Rmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M162PGlEPTB;Nj6xOUDDuSBzLkSyJO69VQ>? M3rGOlI{PzJ7NECy
RMUGS M1zzSGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHjOdIhKSzVyPUeuNFMhyrFiMT64N{DPxE1? M2\NW|I{PzJ7NECy
PEO6 MnToS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlP6TWM2OD15LkC2JOKyKDBwN{Sg{txO M2XO[FI{PzJ7NECy
OVCA429 M{DETWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkDFTWM2OD16LkK5JOKyKDFwNkSg{txO NF;peFMzOzd{OUSwNi=>
OV167 MnvVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWC0e4R4UUN3ME24MlM{KMLzIEGuNVgh|ryP M1TtV|I{PzJ7NECy
RMG1 NYroWZZzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4mwdWlEPTB;OT6zNkDDuSB{LkO2JO69VQ>? NES4[Y0zOzd{OUSwNi=>
OVCAR5 M1v4Tmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUTJR|UxRTlwNUCgxtEhOi53OTFOwG0> M17yTlI{PzJ7NECy
EFO21 M2nqNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3TObWlEPTB;OT65NkDDuSBzLki3JO69VQ>? NH\Y[|czOzd{OUSwNi=>
ES2 M1Xoe2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXPJR|UxRTFyLkGyJOKyKDFwMkOg{txO M{L5SlI{PzJ7NECy
Tyk-nu MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlvvTWM2OD1zMD6yNEDDuSBzLkGyJO69VQ>? MXqyN|czQTRyMh?=
CAOV3 NV\wXY1XT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHnBOnZKSzVyPUGwMlM4KMLzIECuPFch|ryP M4CzRVI{PzJ7NECy
OV207 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVnJR|UxRTF{LkK3JOKyKDBwM{Kg{txO M37CTlI{PzJ7NECy
HEY NWLlXY5RT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXTMVVRpUUN3ME2xN{4xOSEEsTCwMlc2KM7:TR?= MlvkNlM4Ojl2MEK=
DOV13 NU\nb3prT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3nFdmlEPTB-MUWg{txO M3T0UVI{PzJ7NECy
EFO27 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkHSTWM2OD5zNTFOwG0> MljENlM4Ojl2MEK=
HEY C2 M3jGe2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{nmdmlEPTB-MUWg{txO MmLWNlM4Ojl2MEK=
KOC-7cc NVGxWYprT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGLCb5dKSzVyPkG1JO69VQ>? M3HBZ|I{PzJ7NECy
MCASb Mn\HS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXrQcmZ5UUN3ME6xOUDPxE1? NGTtbmIzOzd{OUSwNi=>
OAW42 NHz4dHVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHHuT5FKSzVyPkG1JO69VQ>? M2LmZVI{PzJ7NECy
OV2008 NX3TUJduT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkPCTWM2OD5zNTFOwG0> MXeyN|czQTRyMh?=
OV90 NYDqSWZVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX7ZT|Q1UUN3ME6xOUDPxE1? MoC5NlM4Ojl2MEK=
OVCA420b NV7lRXJnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnLLTWM2OD5zNTFOwG0> MXOyN|czQTRyMh?=
OVCA432 MV\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWryOoZkUUN3ME6xOUDPxE1? M{nUS|I{PzJ7NECy
PEA2 NV\kW291T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYf0U|ZTUUN3ME6xOUDPxE1? M3r5R|I{PzJ7NECy
SKOV3 NIfhOWxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV\JR|UxRjF3IN88US=> NHHhZWUzOzd{OUSwNi=>
TOV112D MnrwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkHmNE0{KM7:TR?= MYDJR|UxRjF3IN88US=> Mor3NlM4Ojl2MEK=
C4-2 M4TsT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3XzdlAuOyEQvF2= NFz2V3IyPCCm MlO2SG1UVw>? MlXt[IVkemWjc3XzJINwdG:weTDueY1j\XJiZH;z[UBl\XCnbnTlcpRtgQ>? NXztN4pSOjN3NkWyOFQ>
PC3 NWXNZoVqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{PqOVAuOyEQvF2= NX2zO|ZOOTRiZB?= NU\LSpNZTE2VTx?= NHfxSJFl\WO{ZXHz[ZMh[2:ub375JI52dWKncjDkc5NmKGSncHXu[IVvfGy7 MVKyN|U3PTJ2NB?=
DU145 NGXkXZlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2jhXFAuOyEQvF2= NYjrVXJsOTRiZB?= M1TDSWROW09? MXfk[YNz\WG|ZYOgZ49td267IH71cYJmeiCmb4PlJIRmeGWwZHXueIx6 MoLoNlM2PjV{NES=
VCaP  MkLuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmPWNE0{KM7:TR?= M4fQT|E1KGR? NYPZeFZmTE2VTx?= M4f0OoRm[3KnYYPld{Bkd2yxbomgcpVu[mW{IHTvd4Uh\GWyZX7k[Y51dHl? Mm\jNlM2PjV{NES=
LNCaP  M1nwTmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4LmRVAuOyEQvF2= MUGxOEBl MojOSG1UVw>? NH\wTGxl\WO{ZXHz[ZMh[2:ub375JI52dWKncjDkc5NmKGSncHXu[IVvfGy7 M3vxO|I{PTZ3MkS0
MDA-MB-468 M3\qSWNmdGxiVnnhZoltcXS7IFHzd4F6 NXLHflhXUUN3ME25Mlch|ryP M3XoZ|IzPjd6MU[x
MDA-MB-231 NEm1WJZE\WyuIG\pZYJqdGm2eTDBd5NigQ>? NGnDRoJKSzVyPUGzJO69VQ>? M4PCN|IzPjd6MU[x
Cal-51 M13EXGNmdGxiVnnhZoltcXS7IFHzd4F6 M1vWWmlEPTB;OD62JO69VQ>? MXiyNlY4QDF4MR?=

... Click to View More Cell Line Experimental Data

In vivo試験 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. [4] 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. [5]
臨床試験 Rucaparib is currently in Phase II clinical trials for locally advanced/metastatic breast or advanced ovarian cancer.
特集 The first PARP inhibitor used in clinical trials combined with temozolomide.

プロトコル (参考用のみ)

キナーゼアッセイ: [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. Ki is calculated by nonlinear regression analysis.
Inhibition of PARP activity Inhibition of PARP activity in 5 × 103 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 immunologica

細胞アッセイ: [4]

細胞株 D425Med, D283Med and D384Med cells
濃度 0.4 μM
反応時間 3 or 5 days
実験の流れ Medulloblastoma cell lines are seeded in 96-well plates at a density of 1 × 103, 3 × 103 and 3 × 103, 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.

動物実験: [4]

動物モデル CD-1 nude mice bearing established D283Med xenografts
製剤 Normal saline
投薬量 1 mg/kg
投与方法 One or four daily by i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Rucaparib (AG-014699,PF-01367338) SDF
分子量 421.36
化学式

C19H18FN3O.H3PO4

CAS No. 459868-92-9
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 84 mg/mL (199.35 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 8-fluoro-5-(4-((methylamino)methyl)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one phosphoric acid

文献中の引用 (14)

技術サポート&よくある質問(FAQ)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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