Tivantinib (ARQ 197)

Tivantinib (ARQ 197)は初めの非ATP競争性的なc-Met阻害剤で、無細胞実験でKi値が0.355 μMです。Tivantinib (ARQ 197)はRonに作用する活性が殆どなくて、EGFR、InsR、PDGFRαとFGFR1/4を抑制する作用がありません。臨床3期。

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Tivantinib (ARQ 197) 化学構造
分子量: 369.42

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製品説明

  • Compare c-Met Inhibitors
    c-Met製品生物活性の比較
  • 研究分野

製品の説明

生物活性

製品説明 Tivantinib (ARQ 197)は初めの非ATP競争性的なc-Met阻害剤で、無細胞実験でKi値が0.355 μMです。Tivantinib (ARQ 197)はRonに作用する活性が殆どなくて、EGFR、InsR、PDGFRαとFGFR1/4を抑制する作用がありません。臨床3期。
ターゲット c-Met
IC50 0.355 μM (Ki) [1]
In vitro試験 ARQ-197 has been shown to prevent HGF/c-met induced cellular responses in vitro. ARQ-197 possesses antitumor activity; inhibiting proliferation of A549, DBTRG and NCI-H441 cells with IC50 of 0.38, 0.45, 0.29 μM. Treatment with ARQ-197 results in a decrease in phosphorylation of the MAPK signaling cascade and prevention of invasion and migration. In addition, ectopic expression of c-Met in NCI-H661, a cell line having no endogenous expression of c-Met, causes it to acquire an invasive phenotype that is also suppressed by ARQ-197. Although the addition of increasing concentrations of ARQ-197 does not significantly affect the Km of ATP, exposure of c-Met to 0.5 μM ARQ-197 decreased the Vmax of c-Met by approximately 3-fold. The ability of ARQ-197 to decrease the Vmax without affecting the Km of ATP confirmed that ARQ-197 inhibits c-Met through a non–ATP-competitive mechanism and may therefore account for its high degree of kinase selectivity. ARQ-197 prevents human recombinant c-Met with a calculated inhibitory constant Ki of approximately 355 nM. Although the highest concentration of ATP used is 200 μM, the potency of ARQ-197 against c-Met is not reduced by using concentrations of ATP up to 1 mM. ARQ-197 blocks c-Met phosphorylation and downstream c-Met signaling pathways. ARQ-197 suppresses constitutive and ligand-mediated c-Met autophosphorylation and, by extension, c-Met activity, in turn leading to the inhibition of downstream c-Met effectors. ARQ-197 induction of caspase-dependent apoptosis is increased in c-Met–expressing human cancer cells including HT29, MKN-45, and MDA-MB-231 cells.[1][2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
MNK-45 NIjQUppMcW6jc3WgZZN{[Xl? MUL+NVAh|ryP NWjrUoVvcW6qaXLpeJMh[y2PZYSgdIhwe3Cqb4L5cIF1cW:wIHHu[EBld3ewc4Ty[YFuKGNvTXX0JJNq\26jbHnu[{Bx[XSqd3H5dy=> NH\3[lYzODR6NECxPC=>
HT29 M2Hq[GtqdmG|ZTDhd5NigQ>? MlGwglExKM7:TR?= M4T2VolvcGmkaYTzJIMuVWW2IIDoc5NxcG:{eXzheIlwdiCjbnSg[I94dnO2cnXhcUBkNU2ndDDzbYdv[WyrbnegdIF1cHejeYO= M370blIxPDh2MEG4
MDA-MB-231 NGXtNm9McW6jc3WgZZN{[Xl? MV\+NVAh|ryP NWewN4RLcW6qaXLpeJMh[y2PZYSgdIhwe3Cqb4L5cIF1cW:wIHHu[EBld3ewc4Ty[YFuKGNvTXX0JJNq\26jbHnu[{Bx[XSqd3H5dy=> NVXhOnJyOjB2OESwNVg>
NCI-H441 M1LiN2tqdmG|ZTDhd5NigQ>? NEHaTpd,OTBizszN MlzlbY5pcWKrdIOgZ{1O\XRicHjvd5Bpd3K7bHH0bY9vKGGwZDDkc5dve3S{ZXHtJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7cx?= NWG3PVlPOjB2OESwNVg>
SK-MEL-28 MYXHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4TVZ|M{KM7:TR?= M3\MOWlEPTB-M{Og{txO MYeyNFQ5PDBzOB?=
NCI-H661 NYn3VVlIT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXqzN{DPxE1? MW\JR|UxRjN|IN88US=> Mn\PNlA1QDRyMUi=
NCI-H446 M{LmZmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M4jNNVM{KM7:TR?= M1\lU2lEPTB;NzFOwG0> NXrvUmRPOjB2OESwNVg>
MDA-MB-231 MnG3S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NUXMcHlkOzNizszN NEXRb2NKSzVyPUCuOVUh|ryP MX:yNFQ5PDBzOB?=
DLD-1 NFHxdnBIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NHTRXHc{OyEQvF2= NWLlPGhPUUN3ME2wMlU{KM7:TR?= M2q0V|IxPDh2MEG4
A549 M4jlbWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NVXMT3ZlOzNizszN MkfmTWM2OD1yLkW5JO69VQ>? M17xZ|IxPDh2MEG4
SK-OV-3 MWHHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NEe5XG8{OyEQvF2= MoTpTWM2OD1yLk[2JO69VQ>? NX;SSFl6OjB2OESwNVg>
NCI-H460 MkLxS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MoGyN|Mh|ryP NVyzeGMxUUN3ME2wMlYh|ryP M2HKXlIxPDh2MEG4
A375 MYPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MVWzN{DPxE1? M1LITWlEPTB;MD60NkDPxE1? MnvKNlA1QDRyMUi=
NCI-H441 MmXHS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NUeyTYdlOzNizszN MV;JR|UxRTBwMzFOwG0> M2HidlIxPDh2MEG4
HT29 NEm0S|VIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NVLIRnN5OzNizszN M2XTOGlEPTB;MD60PUDPxE1? M4GycVIxPDh2MEG4
MKN-45 NF3xUG9Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NUDob5h3OzNizszN Ml:xTWM2OD1yLkW4JO69VQ>? MYSyNFQ5PDBzOB?=
HT29 MUnBdI9xfG:|aYOgZZN{[Xl? MXv+NVAh|ryP MmW3d4lodmmoaXPhcpRtgSCrbnT1Z4V{KGGyb4D0c5NqeyCkeTC4NE06OCVw MXuyNFQ5PDBzOB?=
MKN-45 NX3YWJNPSXCxcITvd4l{KGG|c3H5 M{\DTp4yOCEQvF2= M2fDS5Nq\26rZnnjZY51dHliaX7keYNmeyCjcH;weI9{cXNiYomgPFAuQTBnLh?= M4\B[FIxPDh2MEG4
MDA-MB-231 MlLDRZBweHSxc3nzJIF{e2G7 MmTkglExKM7:TR?= M1L1So1w\GW|dHz5JIlv\HWlZYOgZZBweHSxc3nzJIJ6KDN3JT6= NIPVemwzODR6NECxPC=>
MDA-MB-231/TGL M4\zemdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M4TNXJ4yODBizszN MWTHTVUxRTFwMjFOwG0> MWGyNlAzPzZ7MB?=
1833/TGL NY\jNnlST3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M2j4NZ4yODBizszN NV;WdIRRT0l3ME2zMlch|ryP NFTEc24zOjB{N{[5NC=>
EBC1 M2rBN2N6fG:2b4jpZ:Kh[XO|YYm= Mn;SglExKM7:TR?= NHvvXpdqdmirYnn0d{B1cGViY3XscEBoem:5dHiu MoHzNlM2QTh{N{[=
SNU638 M4G1XmN6fG:2b4jpZ:Kh[XO|YYm= M2HYbp4yOCEQvF2= MWHpcohq[mm2czD0bIUh[2WubDDndo94fGhw NVPOTFgxOjN3OUiyO|Y>
A549 MXvDfZRwfG:6aXRCpIF{e2G7 M{K5SJ4yOCEQvF2= MVTuc5Qh[W[oZXP0 NFKyOmYzOzV7OEK3Oi=>
H460 NWXUeWp4S3m2b4TvfIlkyqCjc4PhfS=> NGi5[nl,OTBizszN NHTFRYpvd3RiYX\m[YN1 MljmNlM2QTh{N{[=
HCC827 MWTDfZRwfG:6aXRCpIF{e2G7 NFuyOZZ,OTBizszN NF7Q[Vhvd3RiYX\m[YN1 M2nMeFI{PTl6Mke2
A549 M3\ZPGZ2dmO2aX;uJIF{e2G7 NYrsRVl{OTBizszN NVLzeG5j\Gm|coXweJMhdWmlcn;0eYJ2dGV? NV[2d3FvOjN3OUiyO|Y>
EBC1 M{PPRWZ2dmO2aX;uJIF{e2G7 NGL6[2IyOCEQvF2= Mkfa[Il{enWydIOgcYlkem:2dXL1cIU> NX\RVXZGOjN3OUiyO|Y>
H460 NILZNoxHfW6ldHnvckBie3OjeR?= NXTXZZFEOTBizszN MVnpcohq[mm2czD0eYJ2dGmwIIDvcJlu\XKrenH0bY9v M3nv[lI2OzF|MEGw
K562/VCR NFz5T2JEgXSxdH;4bYPDqGG|c3H5 NHy0[4h,OTBizszN MlnPd4hwf3NiY4n0c5RwgGmlIHHjeIl3cXS7 NFG4eJIzPTNzM{CxNC=>
CEM/VBL M4XOdmN6fG:2b4jpZ:Kh[XO|YYm= MlrWglExKM7:TR?= NHm4[Y5{cG:5czDjfZRwfG:6aXOgZYN1cX[rdIm= Ml;INlU{OTNyMUC=
U266 M17V[WN6fG:2b4jpZ:Kh[XO|YYm= NGnSbZB,OyEQvF5CpC=> NUKzXZdSUUN3ME2xMlEh|ryP MYKyOVgyODBzMx?=
OPM-2 NV2wfWVOS3m2b4TvfIlkyqCjc4PhfS=> MUf+N{DPxE4EoB?= NXvtUHU4UUN3ME2xMlgh|ryP NVn4TpEzOjV6MUCwNVM>
MM.1S NETUZnpEgXSxdH;4bYPDqGG|c3H5 MYX+N{DPxE4EoB?= M{jRS2lEPTB;MT62JO69VQ>? MXeyOVgyODBzMx?=
MM.1R NHW3W4FIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MmLkN{DPxE4EoB?= NVLxW5g6cW6qaXLpeJMh[2WubDDndo94fGhiYomgOFkm M4S5SFI2QDFyMEGz
RPMI-8226 MXjDfZRwfG:6aXRCpIF{e2G7 MXX+N{DPxE4EoB?= MlL4TWM2OD1yLkmg{txO NHWwVVIzPThzMECxNy=>
ANBL-6 MoDKR5l1d3SxeHnjxsBie3OjeR?= M3:xeVEh|ryPwrC= NF3jV5JqdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=> NX;zdZRbOjV6MUCwNVM>
ANLB-6/V10R Ml\lR5l1d3SxeHnjxsBie3OjeR?= NWm3WnB5OSEQvF5CpC=> MnPvbY5lfWOnczDj[YxtKGSnYYToJIJ6KG2xcnWgeIhidiB3MDW= MmDPNlU5OTByMUO=
KAS-6/1 M2W1NmN6fG:2b4jpZ:Kh[XO|YYm= M{LKUVEh|ryPwrC= Mny4bY5lfWOnczDj[YxtKGSnYYToJIJ6KG2xcnWgeIhidiB3MDW= NXm0SYk6OjV6MUCwNVM>
KAS-6/V10R M2r2Z2N6fG:2b4jpZ:Kh[XO|YYm= NWHQO3FROSEQvF5CpC=> MWXpcoR2[2W|IHPlcIwh\GWjdHigZpkhdW:{ZTD0bIFvKDVyJR?= NUPCW4t3OjV6MUCwNVM>
KAS-6/R10R MoLFR5l1d3SxeHnjxsBie3OjeR?= MlKwNUDPxE4EoB?= MX;pcoR2[2W|IHPlcIwh\GWjdHigZpkhdW:{ZTD0bIFvKDVyJR?= NGDQR48zPThzMECxNy=>
8226/S NVzKfFVFT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MnTEN{DPxE4EoB?= MlS2bY5pcWKrdIOgZ4VtdCCpcn;3eIgh[nliNUSl NX;wOW9XOjV6MUCwNVM>
8226/LR-5 NWTjcHhwT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M4nsZVMh|ryPwrC= MXLpcohq[mm2czDj[YxtKGe{b4f0bEBjgSB3NDW= MUeyOVgyODBzMx?=
Huh7 Mke4R5l1d3SxeHnjxsBie3OjeR?= MmXDglQvQCEQvF5CpC=> NV[yflVSTE2VTx?= M3fwdWlEPTB;OT65JI5O MXuyOlI2QTJ3MB?=
Hep3B NHnyOFVEgXSxdH;4bYPDqGG|c3H5 NX\WbmxzhjRwODFOwG3DqA>? NWTGU25bTE2VTx?= MYPJR|UxRTR2OD63JI5O NVfiS2dFOjZ{NUmyOVA>
HepG2 MVHDfZRwfG:6aXRCpIF{e2G7 MVn+OE45KM7:TdMg MljGSG1UVw>? NVP1[YRGUUN3ME2xN|kvPzdibl2= NHTKd4QzPjJ3OUK1NC=>
Chang NWPYXYV{S3m2b4TvfIlkyqCjc4PhfS=> NVjCSFZ2hjRwODFOwG3DqA>? NF\0PGtFVVOR M{f3cGlEPTB;NES4Mlchdk1? MUGyOlI2QTJ3MB?=
Huh7 MV\GeY5kfGmxbjDhd5NigQ>? MmC4NU43KM7:TdMg MUPEUXNQ NHThR5lk[XW|ZYOgZUBIOi:PIHPlcIwh[3mlbHWgZZJz\XO2 MkLHNlYzPTl{NUC=
Hep3B NXjDdWx3TnWwY4Tpc44h[XO|YYm= MUWxMlYh|ryPwrC= NWP2bZN3TE2VTx?= M2LXboNifXOnczDhJGczN01iY3XscEBkgWOuZTDhdpJme3R? NGHsV3kzPjJ3OUK1NC=>
HepG2 MYjGeY5kfGmxbjDhd5NigQ>? NFjNbFIyNjZizszNxsA> M4[1[2ROW09? MlzVZ4F2e2W|IHGgS|IwVSClZXzsJIN6[2ynIHHydoV{fA>? NFLq[XMzPjJ3OUK1NC=>
Chang Ml7oSpVv[3Srb36gZZN{[Xl? NEnJRWEyNjZizszNxsA> MYrEUXNQ M4\YOINifXOnczDhJGczN01iY3XscEBkgWOuZTDhdpJme3R? NFHqRlUzPjJ3OUK1NC=>
MHCC97L MojIS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MUH+NVAh|ryP NEXNSWxFVVOR NWfHOZViUUN3ME2zNVUhdk1? MV:yOlQ2QDl3Mx?=
MHCC97H MVfHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MUn+NVAh|ryP M2\0[WROW09? NV3hVpU1UUN3ME2zOljjiIlibl2= M3[yWVI3PDV6OUWz
Huh7 M3jSXGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M{Pwe54yOCEQvF2= M1ywPGROW09? Mn3TTWM2OD1{NkWgcm0> M1[zUFI3PDV6OUWz
HepG2 MXrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NWf4dWpDhjFyIN88US=> MYHEUXNQ MoTZTWM2OD1|OUKgcm0> NFfV[FIzPjR3OEm1Ny=>
MHCC97L NUPXO4VpTnWwY4Tpc44h[XO|YYm= NVGwTJZSOSEQvF5CpC=> NXLDWZE2TE2VTx?= M3rESIlv\HWlZYOgcYlkem:2dXL1cIV{KGSncH;sfY1memm8YYTpc44> NWnoWmxGOjZ2NUi5OVM>
Huh7 Ml;pSpVv[3Srb36gZZN{[Xl? NHm4VpkyKM7:TdMg NH7xNHhFVVOR NHv0XINqdmS3Y3XzJI1q[3KxdIXieYxmeyCmZYDvcJlu\XKrenH0bY9v M1mxfFI3PDV6OUWz
MHCC97L NVrYWWdZSXCxcITvd4l{KGG|c3H5 MUSxJO69VcLi NXz1eFRWTE2VTx?= NXXxNog1cW6mdXPld{BieG:ydH;zbZM> MUmyOlQ2QDl3Mx?=
Huh7 NEHYenVCeG:ydH;zbZMh[XO|YYm= Mnf4NUDPxE4EoB?= MkHTSG1UVw>? NYm4VnF4cW6mdXPld{BieG:ydH;zbZM> Ml2yNlY1PTh7NUO=
C3H 10T1/2 mouse fibroblasts Ml7zT4lv[XOnIHHzd4F6 MWSyOUDPxE1? NVmxUJd1TE2VTx?= MYTy[YR2[2W|IFjpd5RwdmViSEOgZY5lKEh2IHHj[ZR6dGG2aX;uJIxmfmWuc9Mg NY\JO3lGOjB3M{SzOFU>
H23 NXfufoxbT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MonNNlUh|ryP MoXiSG1UVw>? MV3zbYdvcW[rY3HueIx6KGmwaHnibZR{KGOnbHyg[5Jwf3SqLh?= NIDJVVYzODV|NEO0OS=>
WM35 NEjPZY1Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MlqxNVAh|ryP MVTEUXNQ Ml\Pd4lodmmoaXPhcpRtgSCrbnjpZol1eyClZXzsJIdzd3e2aD6= MVKyNFU{PDN2NR?=
NIH 3T3 NHTGXXdIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NXXucmNQOTBizszN MVXEUXNQ NH[3Smtld2W|IH7veEBp[X[nIHGgd4lodmmoaXPhcpQhcW6qaXLpeI9zgSCnZn\lZ5Q> MWCyNFU{PDN2NR?=
H838 M3fPcWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M3u5dVExKM7:TR?= MVPEUXNQ M4Xa[YRw\XNibn;0JIhifmViYTDzbYdvcW[rY3HueEBqdmirYnn0c5J6KGWoZnXjeC=> NHr0UYUzODV|NEO0OS=>
H1395 NIHzc5RIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MV[xNEDPxE1? M2PLV2ROW09? MW\kc4V{KG6xdDDoZZZmKGFic3nncolncWOjboSgbY5pcWKrdH;yfUBm\m[nY4S= NGfsd|gzODV|NEO0OS=>
Quiescent S2 M331PGtqdmG|ZTDhd5NigQ>? M3vHO|MxKM7:TR?= MW\EUXNQ MlG3Z49ueGyndHXsfUBi[nKxZ3H0[ZMhXFODLXnu[JVk\WRiaInw[ZJi[2W2eXzheIlwdiCxZjDIN2s1dWV|IHjpd5RwdmW| NXrKZ2I6OjF3MUi5NVU>
PC3 NV36Z5hZSXCxcITvd4l{KGG|c3H5 NUnXWFNMOjBizszN NFOzb2JFVVOR M2rKTIlv\HWlZYOgZZBweHSxc3nz NVT4T5JxOjF5MEmxN|A>
Du145 NHPHUFFCeG:ydH;zbZMh[XO|YYm= NFK5ZVgzOCEQvF2= NWHHW5FxTE2VTx?= NWD5TWRCcW6mdXPld{BieG:ydH;zbZM> NH3PVVUzOTdyOUGzNC=>
LNCaP NIHNTmpCeG:ydH;zbZMh[XO|YYm= NFfCOIYzOCEQvF2= NE\iSlNFVVOR NVXqe2RzcW6mdXPld{BieG:ydH;zbZM> NWjIXHo4OjF5MEmxN|A>
LAPC-4 NE\YXYVCeG:ydH;zbZMh[XO|YYm= M{jVTVIxKM7:TR?= NFf5RVJFVVOR NGfPSXZqdmS3Y3XzJIFxd3C2b4Ppdy=> MWGyNVcxQTF|MB?=
LNCaP M{HqOmZ2dmO2aX;uJIF{e2G7 NYXJSlZSOjBizszN NIWyVGdFVVOR NXjpTWJ5\GWlcnXhd4V{KFCVQTDz[YNz\XSrb36gZY5lKHB4NTDlfJBz\XO|aX;uJIxmfmWucx?= M4\4[|IyPzB7MUOw
LAPC-4 M2jBUmZ2dmO2aX;uJIF{e2G7 M3HwTFIxKM7:TR?= NIPiSGVFVVOR NWLK[3ZQ\GWlcnXhd4V{KFCVQTDz[YNz\XSrb36gZY5lKHB4NTDlfJBz\XO|aX;uJIxmfmWucx?= MYeyNVcxQTF|MB?=
Kasumi-1 M4\YTmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MnHaglUxKM7:TR?= NWTSV2NsTE2VTx?= M{fldYlvcGmkaYTzJINmdGxicILvcIln\XKjdHnvci=> M2TQWFI{OzlyNUO2
SKNO-1 M{O4PGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M{TPVp42OCEQvF2= NXvwXpVYTE2VTx?= MkjjbY5pcWKrdIOgZ4VtdCCycn;sbYZmemG2aX;u NHnCVmszOzN7MEWzOi=>
Kasumi-1 MX;LbY5ie2ViYYPzZZk> NGDmXnB,OTBizszN MoXxSG1UVw>? NFLWcZFz\WS3Y3XzJIV5eHKnc4Ppc44hd2ZiYXPleJlt[XSnZDDobZN1d26nIFizMOKh[y2taYVCpIFv\MLiYnPsMVI> Mn:5NlM{QTB3M{[=
SKNO-1 Mk\UT4lv[XOnIHHzd4F6 NFSxdFN,OTBizszN MlXXSG1UVw>? M3XHVZJm\HWlZYOg[ZhxemW|c3nvckBw\iCjY3X0fYxifGWmIHjpd5RwdmViSEOsxsBkNWurdNMgZY5lyqCkY3ytNi=> M3jRWlI{OzlyNUO2
A549 MonjSpVv[3Srb36gZZN{[Xl? NIHXNHAyOCEQvF2= NVn5fmplTE2VTx?= M2rnd4VvcGGwY3XzJI1qfG:2aXOgZ4F1[XO2cn;wbIU> MYGyOFc1PjV5NB?=
NRK-52E NEOyVZRHfW6ldHnvckBie3OjeR?= NUTpZlIxOTBizszN M4m5SmROW09? NUKzOWFqcW6qaXLpeJMhSW6pIFnJMYlv\HWlZXSgV3RCXDNiboXjcIVieiC2cnHud4xw[2G2aX;uJIFv\CC2aHWg[ZhxemW|c3nvckBw\iCWR1[t{tIyNCClb3zsZYdmdiCLVjDhcoQh\mmkcn;u[YN1cW5? Mlq5NlUxQDhyMEK=
PC12 M17pZWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MV7+NVIvPSEQvF2= MoX0SG1UVw>? MV3wdoV3\W62czDUV2EucW6mdXPl[EBv\XW{aYTlJIZwem2jdHnvci=> NEjVc|gzPTF{OEO4Oi=>
HPMCs MmnFSpVv[3Srb36gZZN{[Xl? M{\2UJJmfmW{c3XzJIVxcXSqZXzpZYwhfG9ibXXz[Y5kcHmvYXygeJJidnOrdHnvckBw\iCqdX3hckBx\XKrdH;u[YFtKG2nc3;0bIVtcWGuIHPlcIx{ MX6yOlA1PTd6MB?=
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MEMM M{fCNmtqdmG|ZTDhd5NigQ>? MlvuNVUhyrWP MojqSG1UVw>? M{fkR4Rm[3KnYYPld{Bi[2W2eXzheIlwdiCxZjDobZN1d26nIFiz MWKyOlkzOTVyNh?=
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ZR-75-1 MWLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? Mm[2NVAh|ryP M3vSfWROW09? M4SzVGlEPTB;N{mgcm0> MWixPFM5OTR2NB?=
BT474 NHrNSFhIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NYLydYZVOTBizszN M{jxXmROW09? NUC4fIpJUUN3ME24OkBvVQ>? M1vBWlE5OzhzNES0
HCC1954 NX[5WpFWT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M4\mT|ExKM7:TR?= M13Sd2ROW09? NU[y[mx[UUN3ME2xNVkhdk1? M3HLb|E5OzhzNES0
MDA-MB-453 NVz6eVNFT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M1v0SVExKM7:TR?= NH:1XFhFVVOR MX7JR|UxRTl5NTDuUS=> NV\NWXoyOTh|OEG0OFQ>
MDA-MB-468 NVyyO|ZvT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NVXKdnZ2OTBizszN MUDEUXNQ MmjYTWM2OD1|MkC4JI5O NVjCZWkxOTh|OEG0OFQ>
SkBr3 M3TXSGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 Ml7aNVAh|ryP Ml3nSG1UVw>? MoT0TWM2OD5zMDywNFAhdk1? Mn\jNVg{QDF2NES=
MDA-MB-231 NFftc5dIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NIrVd2IyOCEQvF2= NXq0[5ZMTE2VTx?= MljCTWM2OD5zMDywNFAhdk1? M13pPFE5OzhzNES0
HCT116 M1X1ZWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MYCxNEDPxE1? MX\EUXNQ M2rWZmlEPTB;NUizOkBvVQ>? M3qyVVE5OzhzNES0
HT29 M3y1T2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 Mn3lNVAh|ryP M4XTbmROW09? NWD4fFN2UUN3ME6xNEwxODBibl2= MUGxPFM5OTR2NB?=
HFF M2OxfGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NXj2bYVrOTBizszN M4jJW2ROW09? NH;hOVhKSzVyPUe2NVUhdk1? MoflNVg{QDF2NES=
HN5 NF\TOW1Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MWCxNEDPxE1? M3X0UmROW09? MU\JR|UxRjFyLECwNEBvVQ>? M12yZVE5OzhzNES0
786-0 Mmn1S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MkTpNVAh|ryP NGLle2xFVVOR M{fzcGlEPTB;NECwPUBvVQ>? Mn7ENVg{QDF2NES=
H157 NVXTS41lT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M3u3ZVExKM7:TR?= MXvEUXNQ NIrXWlVKSzVyPUK2OFIhdk1? MmW5NVg{QDF2NES=
NCI-H460 NGTDXoJIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NWHlVVU{OTBizszN MmfkSG1UVw>? NE\3ZXBKSzVyPkKsOVAxKG6P NFj4bXMyQDN6MUS0OC=>
SKOV-3 NXXQSmtlT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MVmxNEDPxE1? M1zVbWROW09? MY\JR|UxRTJzMk[gcm0> NEPYNHkyQDN6MUS0OC=>
OVCAR-3 MV;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4jCd|ExKM7:TR?= M3K4NmROW09? Ml7hTWM2OD1{OUG4JI5O NIf1NZUyQDN6MUS0OC=>
BXPC3 MlvrS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? M1:3flExKM7:TR?= MlPWSG1UVw>? NHjWVmxKSzVyPUOxOFEhdk1? Mle4NVg{QDF2NES=
MiaPaCa MV;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MlO3NVAh|ryP NEDFdFRFVVOR MnmxTWM2OD13NEOzJI5O MorLNVg{QDF2NES=
PANC-1 MoXoS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? Mn[xNVAh|ryP MnjxSG1UVw>? NXXqZ4xqUUN3ME24OlgyKG6P M2W4V|E5OzhzNES0
LNCaP MnqzS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MmT0NVAh|ryP Mkm0SG1UVw>? NGK1NYtKSzVyPUG0O{BvVQ>? NEmzOoYyQDN6MUS0OC=>
DU145 NGfvWlZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NIXDfYMyOCEQvF2= MmT4SG1UVw>? NILDO2VKSzVyPUO4NVIhdk1? NXvwV5c2OTh|OEG0OFQ>
PC3 MXLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MlS2NVAh|ryP NIfPXnVFVVOR M1TiRmlEPTB-MUCsNFAxKG6P NICwbVYyQDN6MUS0OC=>
BT474 M3excGtqdmG|ZTDhd5NigQ>? NXL0NWJROTBizszN MnjNSG1UVw>? MmXEbY5pcWKrdIOgdGdUUzQQsjD3bZRpKEmFNUCgc4YhOTZyIH7N MXKxPFM5OTR2NB?=
786-0 NUjXXJkzU2mwYYPlJIF{e2G7 MlzVNVAh|ryP M1;YdmROW09? NF\2TpdqdmirYnn0d{BxT1ONM98yJJdqfGhiSVO1NEBw\iBzNUCgcm0> NGfWU4gyQDN6MUS0OC=>
LNCaP MkfET4lv[XOnIHHzd4F6 MYOxNEDPxE1? M3foZWROW09? MlHXbY5pcWKrdIOgdGdUUzQQsjD3bZRpKEmFNUCgc4YhPDNibl2= M4e5TlE5OzhzNES0
PC3 NFHUTpBMcW6jc3WgZZN{[Xl? Ml7xNVAh|ryP MWjEUXNQ M{PUSIlvcGmkaYTzJJBIW0t|zsKge4l1cCCLQ{WwJI9nKDR7IH7N MYWxPFM5OTR2NB?=
KARPAS-231 NH3ENIFIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M3vvVlExKM7:TR?= MV\EUXNQ NHHZVINGSzVyPUSxJI5O NYfsUoo2OTlyNkS3N|A>
CCRFSB M3\I[2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MU[xNEDPxE1? M2nlR2ROW09? Mnz3SWM2OD1zNUWgcm0> NF7ESJkyQTB4NEezNC=>
SUP B15 MlPWS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NVTNSYpDOTBizszN NWntSIVsTE2VTx?= MlrYSWM2OD1zOUegcm0> NWPi[pNZOTlyNkS3N|A>
SD-1 MWDHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MV[xNEDPxE1? MnvySG1UVw>? M2TZfGVEPTB;M{KwJI5O M3;1cVE6ODZ2N{Ow
RS4;11 M13ueWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M2\R[FExKM7:TR?= MYrEUXNQ NUDmO29STUN3ME22OVQhdk1? M1XVVFE6ODZ2N{Ow
MN-60 NFPlUZlIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NHP6fWgyOCEQvF2= NXnUbIYxTE2VTx?= MVjFR|UxRTN4MEKgcm0> M3Oz[lE6ODZ2N{Ow
Tanoue NIHuVHJIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M3PyWlExKM7:TR?= MoDUSG1UVw>? NEGycZRGSzVyPUS1NVchdk1? NUPpNZFoOTlyNkS3N|A>
RCH-ACV NX7kb3V{T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M3Xqc|ExKM7:TR?= MmL5SG1UVw>? NYrGUnBrTUN3ME2xOVIhdk1? M2\NclE6ODZ2N{Ow
SEM M2r6RWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MkPwNVAh|ryP M1fScWROW09? MkLjSWM2OD1{MEKgcm0> Mk\pNVkxPjR5M{C=
KASUMI-2 M2jtXWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MnLNNVAh|ryP NI\yO3BFVVOR M3y3b2VEPTB;MkK1JI5O MoTZNVkxPjR5M{C=
REH MXPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MVOxNEDPxE1? NFj4XWVFVVOR NWHoSo9VTUN3ME2yPFghdk1? NFmzfY0yQTB4NEezNC=>
697 MoDKS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? M4XDXlExKM7:TR?= NXHkOGhiTE2VTx?= NYGxVm5oTUN3ME2zN|ghdk1? M3HQSFE6ODZ2N{Ow
NALM-6 NGPIR2lIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NES5bG4yOCEQvF2= NIT6fIxFVVOR MVLFR|UxRTR{MTDuUS=> MWexPVA3PDd|MB?=
MHH-CALL–3 NGTIW5RIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NXTVUWIzOTBizszN NFHvU4tFVVOR M3zsemVEPTB;OEGyJI5O NG\TeXEyQTB4NEezNC=>
MHH-CALL–2 MVTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NUjM[2E{OTBizszN M4X6fmROW09? MX\FR|UxRTJzMUSgcm0> NEjpRW0yQTB4NEezNC=>
J.GAMMA-1 NGHWZ4xIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MXexNEDPxE1? NEC3emRFVVOR NGrVfIdGSzVyPU[1JI5O NH[wNW4yQTB4NEezNC=>
JR45.01 MX3Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MljiNVAh|ryP NF63PJpFVVOR MXjFR|UxRTZ6IH7N M1qwVFE6ODZ2N{Ow
A3 NETFflVIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NEXVN3IyOCEQvF2= M2\sTWROW09? NVLUbXFLTUN3ME22PUBvVQ>? M4T0[FE6ODZ2N{Ow
I 2.1 MkHGS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NX20SnV3OTBizszN NVrqVWU6TE2VTx?= M3;YSmVEPTB;N{Ogcm0> MXuxPVA3PDd|MB?=
MOLT-3 NY\ERpZiT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MX2xNEDPxE1? MXvEUXNQ M1O0XGVEPTB;N{Sgcm0> NU\O[mlYOTlyNkS3N|A>
P116 NUO2NnpRT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M2HhUVExKM7:TR?= NGH6XJRFVVOR NG\JVWdGSzVyPUe4JI5O NV;qXHFwOTlyNkS3N|A>
J.Cam1.6 NHnGdmhIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MXWxNEDPxE1? MWLEUXNQ NHrPdW5GSzVyPUe5JI5O MVyxPVA3PDd|MB?=
I 9.2 NH7HWnRIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MoWzNVAh|ryP M4G4[WROW09? NXzRbW9[TUN3ME24NEBvVQ>? NGnuXoIyQTB4NEezNC=>
LOUCY MWjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MnzQNVAh|ryP NFrHTIpFVVOR NYT3VGl5TUN3ME2xNVchdk1? NFO1cG4yQTB4NEezNC=>
J.RT3-T3.5 MYTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NHHMVo4yOCEQvF2= M3;KZWROW09? NW\6[WdKTUN3ME2xNlMhdk1? M3X2VFE6ODZ2N{Ow
800000 NVvZNohUT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NETsSYQyOCEQvF2= MVvEUXNQ NWjxVnZSTUN3ME2xOlMhdk1? NFPoRYoyQTB4NEezNC=>
Jurkat MXzHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M1rybVExKM7:TR?= NGO1[plFVVOR NXXVPVVHTUN3ME2yNlUhdk1? NHnBXHIyQTB4NEezNC=>
MOLT-4 MUfHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MX:xNEDPxE1? MWTEUXNQ MmrqSWM2OD1{M{Kgcm0> NHLBUHEyQTB4NEezNC=>
Molt-16 M1r1bGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MnjlNVAh|ryP NYTwRoNQTE2VTx?= MXLFR|UxRTJ2MTDuUS=> NGHZW3oyQTB4NEezNC=>
CEM/C3 MXzHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NULLVYJ2OTBizszN NXTsVWc2TE2VTx?= NV:2bIFzTUN3ME2yOVchdk1? NH7tN3AyQTB4NEezNC=>
CEM/C2 NEnxW|NIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NGeyfVEyOCEQvF2= M1XscGROW09? MYDFR|UxRTJ5MTDuUS=> MX2xPVA3PDd|MB?=
CCRFCEM NGjRNmlIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MWmxNEDPxE1? MYfEUXNQ M{D2cWVEPTB;M{K3JI5O NEiyb5UyQTB4NEezNC=>
CEM/C1 NIfPcJNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M1i1R|ExKM7:TR?= M3X2O2ROW09? M4S4cmVEPTB;M{iyJI5O M{LLblE6ODZ2N{Ow
SUPTI[VB] M{\JSWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 Ml;PNVAh|ryP MnPNSG1UVw>? Mn6ySWM2OD14MUmgcm0> Ml63NVkxPjR5M{C=
CCRF–HSB-2 NYK4RlZQT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NHHMSY0yOCEQvF2= MXPEUXNQ M1vpcGVEPTB;MkGxO{BvVQ>? MUKxPVA3PDd|MB?=
I 2.1 MWLBdI9xfG:|aYOgZZN{[Xl? NH;USYcyOCEQvF2= M3;CcmROW09? Ml\0bY5lfWOnczDhdI9xfG:|aYO= NYXrPW1yOTlyNkS3N|A>
I 9.2 NYTxR49KSXCxcITvd4l{KGG|c3H5 NYDDem0{OTBizszN NHPwPVNFVVOR NUS0T5VpcW6mdXPld{BieG:ydH;zbZM> MYexPVA3PDd|MB?=
A3 NW\DTpR{SXCxcITvd4l{KGG|c3H5 M1zCeVExKM7:TR?= MoiwSG1UVw>? MnjZbY5lfWOnczDhdI9xfG:|aYO= Mki1NVkxPjR5M{C=
RD NVXtVJJUT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MWSxNEDPxE1? NV7nb|JRUUN3ME6xNEDPxE1? MWqyNFc1ODZ{Mx?=
Rh41 MX\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NHnhXmMyOCEQvF2= NI\CTlRKSzVyPUOzMlghdk1? MXiyNFc1ODZ{Mx?=
Rh18 MV;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M2XPVVExKM7:TR?= NEjoTYxKSzVyPUOwN{BvVQ>? MmH5NlA4PDB4MkO=
Rh30 NETVd41Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= Mn\BNVAh|ryP MYrJR|UxRTRwOEGg{txO NHWxZ4czODd2ME[yNy=>
BT-12 NHrMV4pIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M{HlV|ExKM7:TR?= NYHHO4xIUUN3ME6xNEDPxE1? MlPDNlA4PDB4MkO=
CHLA-266 NEHTc|lIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M2WwWFExKM7:TR?= NVX1dmNmUUN3ME2xMlIzKM7:TR?= MXSyNFc1ODZ{Mx?=
TC-71 NFjnXlBIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MWCxNEDPxE1? NVTCN|l[UUN3ME2yMlUzKM7:TR?= NEXM[lUzODd2ME[yNy=>
CHLA-9 MX\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M{fw[FExKM7:TR?= M4C4W2lEPTB;NUmxJI5O MlPUNlA4PDB4MkO=
CHLA-10 MorQS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NWnyOVhEOTBizszN M{ntXmlEPTB;MUCyJI5O MnvRNlA4PDB4MkO=
CHLA-258 NGq0SI5Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MVSxNEDPxE1? MV;JR|UxRTFwMEWg{txO M2P1R|IxPzRyNkKz
GBM2 M4DsZWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M4fEPFExKM7:TR?= MoTVTWM2OD17LkG1JO69VQ>? Mn\2NlA4PDB4MkO=
NB-1643 M1HqU2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NX\LSHFTOTBizszN NVW2cYFUUUN3ME21MlQh|ryP Mlv1NlA4PDB4MkO=
NB-Ebc1 MkfmS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MYSxNEDPxE1? M{nyZWlEPTB-MUCg{txO MmrpNlA4PDB4MkO=
CHLA-90 M4fqOWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M3zaN|ExKM7:TR?= MXjJR|UxRjFyIN88US=> MU[yNFc1ODZ{Mx?=
CHLA-136 MUPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4fKcVExKM7:TR?= NFnYXVBKSzVyPkGwJO69VQ>? NEO3eowzODd2ME[yNy=>
NALM-6 MkfQS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NETr[|YyOCEQvF2= MXXJR|UxRTJ4NTDuUS=> M2H2XFIxPzRyNkKz
COG-LL-317 NF;RVVBIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NYXPSnc2OTBizszN NGO3UmJKSzVyPU[uOFkhdk1? M3fG[|IxPzRyNkKz
RS4;11 MUDHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M1nmPFExKM7:TR?= MWLJR|UxRTF2NzDuUS=> MYeyNFc1ODZ{Mx?=
MOLT-4 MmD2S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NGHDfnMyOCEQvF2= MVPJR|UxRTRyIH7N NVrRO3NxOjB5NEC2NlM>
CCRF-CEM NYfhOFlST3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NEXXfVgyOCEQvF2= M1H6cGlEPTB;Mk[4JI5O NUPI[YZOOjB5NEC2NlM>
Kasumi-1 Mn\2S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? M2OyclExKM7:TR?= M1PDZmlEPTB;MUC3JI5O MXWyNFc1ODZ{Mx?=
Karpas-299 MXPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NUS3SoNEOTBizszN M3jz[GlEPTB;Mj65N{DPxE1? NU\xdVR[OjB5NEC2NlM>
Ramos-RA1 MWLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MWmxNEDPxE1? NEHG[2JKSzVyPUeuN|Uh|ryP MkS1NlA4PDB4MkO=
H1299 MoXWT4lv[XOnIHHzd4F6 NW[4V25LOTBizszN MUPpcohq[mm2czDJT2JMTS2rbnT1Z4VlKEGtdDDBZ5RqfmG2aX;u NXzSdWl1OjF7MEi2NVY>

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In vivo試験 All three xenograft models treated with ARQ-197 display reductions in tumor growth: 66% in the HT29 model, 45% in the MKN-45 model, and 79% in the MDA-MB-231 model. In these xenograft studies, no significant body weight changes following oral administration of ARQ-197 at 200 mg/kg are observed. Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by ARQ-197, as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of ARQ-197. This same dosage in mice exhibits that tumor xenografts are exposed to sustained plasma levels of ARQ-197, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. Plasma levels of ARQ-197 10 hours after dosing are determined to be 1.3 μM, more than 3-fold above the biochemical inhibitory constant of ARQ-197 for c-Met. Therefore, ARQ-197 is able to suppress its target in vivo in the xenografted human tumor tissue. In conclusion, ARQ-197 inhibits the growth of c-Met-dependent xenografted human tumors.[1]
臨床試験 ARQ 197 plus erlotinib is currently in Phase III study in subjects with locally advanced or metastatic non-squamous, non-small cell lung cancer who have received 1 or 2 prior systemic anti-cancer therapies.
特集 The first selective c-Met inhibitor to be advanced into human clinical trials.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

c-Met SDS-PAGE in vitro kinase assay Recombinant c-Met protein (100 ng) is preincubated with increasing concentrations of ARQ-197 for 30 minutes at room temperature. Following preincubation, 100 μM of poly-Glu-Tyr substrate and various concentrations of ATP containing 5 μCi of [γ-32P]ATP are added to the reaction mixture. The reaction is incubated for 5 minutes at room temperature and then stopped by the addition of 5 μL of SDS-polyacrylamide gel, reducing sample buffer. The samples are then loaded onto a 7.5% acrylamide gel and SDS-PAGE is performed. The phosphorylated poly-Glu-Tyr substrates are ultimately visualized by autoradiography. c-Met activity is quantified by densitometry.

細胞アッセイ: [1]

細胞株 T29, MKN-45 and MDA-MB-231 cells
濃度 0.03-10 μM
反応時間 24, 32, and 48 hours
実験の流れ HT29, MKN-45, and MDA-MB-231 cells are seeded in black 96-well plates at 5 × 103 cells per well overnight in a medium with 10% FBS. The next day, cells are treated with increasing concentrations of ARQ-197 (0.03-10 μM) for 24, 32, and 48 hours at 37 °C. After ARQ-197 treatment, the drug-containing medium is removed and cells are incubated for at least 10 minutes in a labeling solution (10 mM HEPES, 140 mM NaCl, and 6 mM CaCl2) containing 2 μg/mL Hoescht 33342 (blue channel), 500-times diluted Annexin V-FITC (green channel), and 1 μg/mL propidium iodide (red channel). High-content image acquisition and analysis are carried out. The program is set to take four images per well. The exposure time is set at 16.7 ms/10% gain, 500 ms/35% gain, and 300 ms/30% gain for the 4,6-diamidino-2-phenylindole, FITC, and rhodamine channels, respectively. Images are processed and the numbers of positive cells for each channel and each condition are determined. In addition, HT29 cells are treated with increasing concentrations of ARQ-197 for 32 hours in the absence or the presence of 25, 50, and 100 μM ZvAD-FMK (irreversible general caspase inhibitor), and the same procedures are undertaken. All experiments are done in triplicate. To determine whether the apoptotic effect is due to c-Met inhibition, the effect of ARQ-197 when glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and c-Met are knocked down using siRNA is investigated. HT29, MKN-45, and MDA-MB-231 cells are transfected with a nontargeted control siRNA, a gapgh-targeted control siRNA, or a met-targeted siRNA. After 3 days, c-Met, GAPDH, and β-actin expression levels are determined using specific antibodies. To determine if the effect is caspase dependent, HT29, MKN-45, and MDA-MB-231 cells are transfected with a met-targeted siRNA for 2 days and incubated in the absence or the presence of increasing concentrations of ZvAD-FMK for 1 additional day. A nontargeted siRNA and a gapgh-targeted siRNA (siRNA GAPDH) are also transfected in parallel, as controls. Cells are then stained with Annexin V-FITC and propidium iodide, and the percentage of apoptotic cells is determined.

動物実験: [1]

動物モデル Female athymic nude mice bearing HT29, MKN-45, or MDA-MB-231 tumor xenografts
製剤 In polyethylene glycol 400/20% Vitamin E tocopheryl polyethylene glycol succinate (60:40) 30 mg/mL
投薬量 200 mg/kg
投与方法 Orally administered

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 Tivantinib (ARQ 197) SDF
分子量 369.42
化学式

C23H19N3O2

CAS No. 905854-02-6
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 73 mg/mL (197.6 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo
* <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 (3R,4R)-3-(2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione

文献中の引用 (4)

Frequently Asked Questions

  • Question 1
    Are there any other solutions (apart from DMSO) I can dissolve S2753 for in vivo experiment?

    Answer: S2753 Tivantinib (ARQ 197) can be dissolved in 1% methylcellulose at15 mg/ml as a suspension.

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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