Tivantinib (ARQ 197)

For research use only.

Catalog No.S2753

33 publications

Tivantinib (ARQ 197) Chemical Structure

CAS No. 905854-02-6

Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Tivantinib (ARQ 197) induces a G2/M arrest and apoptosis. Phase 3.

Selleck's Tivantinib (ARQ 197) has been cited by 33 publications

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Choose Selective c-Met Inhibitors

Biological Activity

Description Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Tivantinib (ARQ 197) induces a G2/M arrest and apoptosis. Phase 3.
Features The first selective c-Met inhibitor to be advanced into human clinical trials.
Targets
c-Met [1]
(Cell-free assay)
0.355 μM(Ki)
In vitro

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 Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MNK-45 MWrLbY5ie2ViYYPzZZk> NYTDbIRnhjFyIN88US=> MlP3bY5pcWKrdIOgZ{1O\XRicHjvd5Bpd3K7bHH0bY9vKGGwZDDkc5dve3S{ZXHtJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7cx?= MkPpNlA1QDRyMUi=
HT29 NIqyS4RMcW6jc3WgZZN{[Xl? M2jLb54yOCEQvF2= Mo\xbY5pcWKrdIOgZ{1O\XRicHjvd5Bpd3K7bHH0bY9vKGGwZDDkc5dve3S{ZXHtJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7cx?= NEXreJMzODR6NECxPC=>
MDA-MB-231 MU\LbY5ie2ViYYPzZZk> MXr+NVAh|ryP NW\iRXNRcW6qaXLpeJMh[y2PZYSgdIhwe3Cqb4L5cIF1cW:wIHHu[EBld3ewc4Ty[YFuKGNvTXX0JJNq\26jbHnu[{Bx[XSqd3H5dy=> MY[yNFQ5PDBzOB?=
NCI-H441 NH;0Z2lMcW6jc3WgZZN{[Xl? MkjTglExKM7:TR?= M4[1eYlvcGmkaYTzJIMuVWW2IIDoc5NxcG:{eXzheIlwdiCjbnSg[I94dnO2cnXhcUBkNU2ndDDzbYdv[WyrbnegdIF1cHejeYO= MkHkNlA1QDRyMUi=
SK-MEL-28 NV3YXphmT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MlLEN|Mh|ryP M4X5NWlEPTB-M{Og{txO NH3NO44zODR6NECxPC=>
NCI-H661 NGLUUo5Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NGL3d|I{OyEQvF2= MV7JR|UxRjN|IN88US=> NVvTRWZvOjB2OESwNVg>
NCI-H446 NYrSNJA6T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MYezN{DPxE1? Mn;iTWM2OD15IN88US=> Ml25NlA1QDRyMUi=
MDA-MB-231 MoP6S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? Ml[zN|Mh|ryP NF3QW4FKSzVyPUCuOVUh|ryP M2PBUlIxPDh2MEG4
DLD-1 MnjPS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MXizN{DPxE1? M2nB[WlEPTB;MD61N{DPxE1? MoDKNlA1QDRyMUi=
A549 MVvHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NWnteXA5OzNizszN NGHhSIFKSzVyPUCuOVkh|ryP MXmyNFQ5PDBzOB?=
SK-OV-3 M2fpNmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NUX5[W1EOzNizszN MnnXTWM2OD1yLk[2JO69VQ>? NVfnNHBHOjB2OESwNVg>
NCI-H460 NXXPWVVJT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NHHNPXI{OyEQvF2= NYGySYFlUUN3ME2wMlYh|ryP M{H5V|IxPDh2MEG4
A375 MYnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4nNZ|M{KM7:TR?= MWLJR|UxRTBwNEKg{txO M1G3[|IxPDh2MEG4
NCI-H441 NWXKdXl5T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXqzN{DPxE1? NHrPNHNKSzVyPUCuN{DPxE1? MV6yNFQ5PDBzOB?=
HT29 M3nMNWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NGjCTVM{OyEQvF2= MW\JR|UxRTBwNEmg{txO NHH5XJIzODR6NECxPC=>
MKN-45 M3vy[mdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MXKzN{DPxE1? M4XVfmlEPTB;MD61PEDPxE1? NVHROot2OjB2OESwNVg>
HT29 M3\FOWFxd3C2b4Ppd{Bie3OjeR?= NUjzNXN{hjFyIN88US=> MWHzbYdvcW[rY3HueIx6KGmwZIXj[ZMh[XCxcITvd4l{KGK7IEiwMVkxLS5? NHjrUlQzODR6NECxPC=>
MKN-45 NEjIdmpCeG:ydH;zbZMh[XO|YYm= MWr+NVAh|ryP MoXXd4lodmmoaXPhcpRtgSCrbnT1Z4V{KGGyb4D0c5NqeyCkeTC4NE06OCVw NEXZWGwzODR6NECxPC=>
MDA-MB-231 NG\oWZZCeG:ydH;zbZMh[XO|YYm= NX\GTIZThjFyIN88US=> NIn6cIVud2Snc4TsfUBqdmS3Y3XzJIFxd3C2b4Ppd{BjgSB|NTWu MlfSNlA1QDRyMUi=
MDA-MB-231/TGL MYjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NXPu[ndDhjFyMDFOwG0> NF7VOVZIUTVyPUGuNkDPxE1? M2P4RVIzODJ5Nkmw
1833/TGL MVLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M2jDZ54yODBizszN M3L1TWdKPTB;Mz63JO69VQ>? M3Tue|IzODJ5Nkmw
EBC1 MWTDfZRwfG:6aXRCpIF{e2G7 MnzCglExKM7:TR?= NIL0VHhqdmirYnn0d{B1cGViY3XscEBoem:5dHiu MknINlM2QTh{N{[=
SNU638 NIi3ZYJEgXSxdH;4bYPDqGG|c3H5 NFfpTXZ,OTBizszN NH;MfFZqdmirYnn0d{B1cGViY3XscEBoem:5dHiu NWPFfZF5OjN3OUiyO|Y>
A549 MkPkR5l1d3SxeHnjxsBie3OjeR?= MnLZglExKM7:TR?= NVj5N5Izdm:2IHHm[oVkfA>? M1X3XFI{PTl6Mke2
H460 MoXlR5l1d3SxeHnjxsBie3OjeR?= MVj+NVAh|ryP MX3uc5Qh[W[oZXP0 M{PiNFI{PTl6Mke2
HCC827 NWTzeINGS3m2b4TvfIlkyqCjc4PhfS=> Mk\XglExKM7:TR?= NVvIeoZEdm:2IHHm[oVkfA>? NILmSlUzOzV7OEK3Oi=>
A549 NIf4O5lHfW6ldHnvckBie3OjeR?= M324VFExKM7:TR?= NFz4dFhlcXO{dYD0d{BucWO{b4T1ZpVt\Q>? MWWyN|U6QDJ5Nh?=
EBC1 MUjGeY5kfGmxbjDhd5NigQ>? NFjt[5QyOCEQvF2= Ml3u[Il{enWydIOgcYlkem:2dXL1cIU> NH\6UWozOzV7OEK3Oi=>
H460 NYnzU2FnTnWwY4Tpc44h[XO|YYm= M2XibFExKM7:TR?= M37GUYlvcGmkaYTzJJR2[nWuaX6gdI9tgW2ncnn6ZZRqd25? MX[yOVMyOzBzMB?=
K562/VCR M2\oOWN6fG:2b4jpZ:Kh[XO|YYm= M2TDZZ4yOCEQvF2= M{\wRZNpd3e|IHP5eI91d3irYzDhZ5Rqfmm2eR?= NWDwWoZEOjV|MUOwNVA>
CEM/VBL M4DzSWN6fG:2b4jpZ:Kh[XO|YYm= MYT+NVAh|ryP NVLBN49Ze2ixd4OgZ5l1d3SxeHnjJIFkfGm4aYT5 MWiyOVMyOzBzMB?=
U266 NX25bm02S3m2b4TvfIlkyqCjc4PhfS=> NWexUlFMhjNizszNxsA> MoewTWM2OD1zLkGg{txO NXLFeXRxOjV6MUCwNVM>
OPM-2 NI[3OWtEgXSxdH;4bYPDqGG|c3H5 MXv+N{DPxE4EoB?= NV:2Zo9GUUN3ME2xMlgh|ryP M3PDOFI2QDFyMEGz
MM.1S M1nDU2N6fG:2b4jpZ:Kh[XO|YYm= MmewglMh|ryPwrC= NUC2Vo1KUUN3ME2xMlYh|ryP MUmyOVgyODBzMx?=
MM.1R M1T5Nmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M4nxd|Mh|ryPwrC= NIPyR3BqdmirYnn0d{Bk\WyuIHfyc5d1cCCkeTC0PUU> NEf1N5czPThzMECxNy=>
RPMI-8226 M4PaUWN6fG:2b4jpZ:Kh[XO|YYm= Mm\oglMh|ryPwrC= M4P2eWlEPTB;MD65JO69VQ>? NVS3UFl4OjV6MUCwNVM>
ANBL-6 NGL0c2VEgXSxdH;4bYPDqGG|c3H5 MVGxJO69VcLi NHrIfItqdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=> NWL6bmRHOjV6MUCwNVM>
ANLB-6/V10R MVPDfZRwfG:6aXRCpIF{e2G7 NUPqS4Z[OSEQvF5CpC=> M4XvWYlv\HWlZYOgZ4VtdCCmZXH0bEBjgSCvb4LlJJRp[W5iNUCl MkLqNlU5OTByMUO=
KAS-6/1 M{LPWGN6fG:2b4jpZ:Kh[XO|YYm= NIHOV|MyKM7:TdMg NGOwSm5qdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=> MkDGNlU5OTByMUO=
KAS-6/V10R M2TZUWN6fG:2b4jpZ:Kh[XO|YYm= M2q0dVEh|ryPwrC= NIGxRYhqdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=> MoDLNlU5OTByMUO=
KAS-6/R10R M4DrWWN6fG:2b4jpZ:Kh[XO|YYm= MV2xJO69VcLi MWTpcoR2[2W|IHPlcIwh\GWjdHigZpkhdW:{ZTD0bIFvKDVyJR?= Mm\1NlU5OTByMUO=
8226/S MnziS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MV6zJO69VcLi MmLHbY5pcWKrdIOgZ4VtdCCpcn;3eIgh[nliNUSl MX2yOVgyODBzMx?=
8226/LR-5 NUPGT49uT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXizJO69VcLi MX7pcohq[mm2czDj[YxtKGe{b4f0bEBjgSB3NDW= MYqyOVgyODBzMx?=
Huh7 MnW1R5l1d3SxeHnjxsBie3OjeR?= NI[5XI1,PC56IN88UeKh MVjEUXNQ Mn\2TWM2OD17Lkmgcm0> NVrHXIk{OjZ{NUmyOVA>
Hep3B NU\WR2o{S3m2b4TvfIlkyqCjc4PhfS=> NGPyfYd,PC56IN88UeKh MW\EUXNQ MVPJR|UxRTR2OD63JI5O M2[xRlI3OjV7MkWw
HepG2 NEW2fmREgXSxdH;4bYPDqGG|c3H5 MUP+OE45KM7:TdMg NHrjZVhFVVOR MYLJR|UxRTF|OT63O{BvVQ>? M4K0PFI3OjV7MkWw
Chang NU\vcHhlS3m2b4TvfIlkyqCjc4PhfS=> MkTNglQvQCEQvF5CpC=> M3rITmROW09? MlPrTWM2OD12NEiuO{BvVQ>? NIDzbVIzPjJ3OUK1NC=>
Huh7 Mn7tSpVv[3Srb36gZZN{[Xl? M1vFeVEvPiEQvF5CpC=> MnnySG1UVw>? MYDjZZV{\XNiYTDHNk9OKGOnbHygZ5lkdGViYYLy[ZN1 NVHoO5RSOjZ{NUmyOVA>
Hep3B M1joOWZ2dmO2aX;uJIF{e2G7 MUexMlYh|ryPwrC= MWPEUXNQ MlzjZ4F2e2W|IHGgS|IwVSClZXzsJIN6[2ynIHHydoV{fA>? MYKyOlI2QTJ3MB?=
HepG2 MWLGeY5kfGmxbjDhd5NigQ>? M4fUNFEvPiEQvF5CpC=> NWH1cZltTE2VTx?= MmTOZ4F2e2W|IHGgS|IwVSClZXzsJIN6[2ynIHHydoV{fA>? NFT6WoMzPjJ3OUK1NC=>
Chang M1PDVGZ2dmO2aX;uJIF{e2G7 NXnHcVBlOS54IN88UeKh MoPmSG1UVw>? NHjXfIdk[XW|ZYOgZUBIOi:PIHPlcIwh[3mlbHWgZZJz\XO2 NVTUPZhFOjZ{NUmyOVA>
MHCC97L Mn3aS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? M1z6Xp4yOCEQvF2= MoTtSG1UVw>? NFPCTXJKSzVyPUOxOUBvVQ>? NXrMeYY4OjZ2NUi5OVM>
MHCC97H MVrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NF;uNFl,OTBizszN NHP5TpFFVVOR M4TZPGlEPTB;M{[45qCKKG6P NEDoSHYzPjR3OEm1Ny=>
Huh7 MVfHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NH;mZol,OTBizszN M1nKXGROW09? NWnYXYs4UUN3ME2yOlUhdk1? M1;kcVI3PDV6OUWz
HepG2 MmCwS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MkfBglExKM7:TR?= NH;rXpNFVVOR M2LkXWlEPTB;M{myJI5O MUOyOlQ2QDl3Mx?=
MHCC97L NEDyRVhHfW6ldHnvckBie3OjeR?= M1nCcFEh|ryPwrC= MX7EUXNQ NWq4RoJFcW6mdXPld{BucWO{b4T1ZpVt\XNiZHXwc4x6dWW{aYrheIlwdg>? MVKyOlQ2QDl3Mx?=
Huh7 M1K4UGZ2dmO2aX;uJIF{e2G7 MmXRNUDPxE4EoB?= M4DhfGROW09? MV;pcoR2[2W|IH3pZ5JwfHWkdXzld{Bl\XCxbInt[ZJqgmG2aX;u MY[yOlQ2QDl3Mx?=
MHCC97L MXTBdI9xfG:|aYOgZZN{[Xl? NILIV3IyKM7:TdMg NX:2d29JTE2VTx?= MoC0bY5lfWOnczDhdI9xfG:|aYO= NYP2N2F1OjZ2NUi5OVM>
Huh7 NYLhenRHSXCxcITvd4l{KGG|c3H5 MWGxJO69VcLi MWTEUXNQ MlnIbY5lfWOnczDhdI9xfG:|aYO= NUfvR3B{OjZ2NUi5OVM>
C3H 10T1/2 mouse fibroblasts NVW2b5BmU2mwYYPlJIF{e2G7 M{PWTFI2KM7:TR?= MV3EUXNQ NIHOOWhz\WS3Y3XzJGhqe3SxbnWgTFMh[W6mIFi0JIFk\XS7bHH0bY9vKGyndnXsd:Kh NXvXW|B6OjB3M{SzOFU>
H23 MXLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NFSwc|QzPSEQvF2= Ml25SG1UVw>? M4jvfZNq\26rZnnjZY51dHliaX7obYJqfHNiY3XscEBoem:5dHiu NIK3Z3EzODV|NEO0OS=>
WM35 MmjiS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NEi0cY4yOCEQvF2= MlixSG1UVw>? Mn36d4lodmmoaXPhcpRtgSCrbnjpZol1eyClZXzsJIdzd3e2aD6= M3qx[|IxPTN2M{S1
NIH 3T3 NWnyUmtET3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NH;JRWsyOCEQvF2= Mn3RSG1UVw>? NUe0cpZ5\G:nczDuc5QhcGG4ZTDhJJNq\26rZnnjZY51KGmwaHnibZRwenliZX\m[YN1 Ml;qNlA2OzR|NEW=
H838 NV3LeoN1T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MkexNVAh|ryP NX\6V4ZbTE2VTx?= Moq5[I9meyCwb4SgbIF3\SCjIIPp[45q\mmlYX70JIlvcGmkaYTvdpkh\W[oZXP0 MUeyNFU{PDN2NR?=
H1395 NVrHSVEyT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXGxNEDPxE1? M17Sd2ROW09? MlTy[I9meyCwb4SgbIF3\SCjIIPp[45q\mmlYX70JIlvcGmkaYTvdpkh\W[oZXP0 NH7jbW8zODV|NEO0OS=>
Quiescent S2 NVK2[HhCU2mwYYPlJIF{e2G7 NFP4T40{OCEQvF2= MV\EUXNQ MmXvZ49ueGyndHXsfUBi[nKxZ3H0[ZMhXFODLXnu[JVk\WRiaInw[ZJi[2W2eXzheIlwdiCxZjDIN2s1dWV|IHjpd5RwdmW| Mkj0NlE2OTh7MUW=
PC3 NEXZSlNCeG:ydH;zbZMh[XO|YYm= MnHWNlAh|ryP NU\3OZVKTE2VTx?= M{TFOYlv\HWlZYOgZZBweHSxc3nz M3HmUVIyPzB7MUOw
Du145 M1yxeGFxd3C2b4Ppd{Bie3OjeR?= M4DocFIxKM7:TR?= MWHEUXNQ Mo\NbY5lfWOnczDhdI9xfG:|aYO= MX:yNVcxQTF|MB?=
LNCaP MWPBdI9xfG:|aYOgZZN{[Xl? MmnvNlAh|ryP MkW2SG1UVw>? NGftW49qdmS3Y3XzJIFxd3C2b4Ppdy=> MViyNVcxQTF|MB?=
LAPC-4 MorPRZBweHSxc3nzJIF{e2G7 MV[yNEDPxE1? NWPhfnVNTE2VTx?= Mn\RbY5lfWOnczDhdI9xfG:|aYO= M1fKOVIyPzB7MUOw
LNCaP NUTqRXdUTnWwY4Tpc44h[XO|YYm= M4jlWVIxKM7:TR?= MmHYSG1UVw>? MVzk[YNz\WG|ZYOgVHNCKHOnY4LleIlwdiCjbnSgdFY2KGW6cILld5Nqd25ibHX2[Yx{ NEX1fGEzOTdyOUGzNC=>
LAPC-4 NFf0ZZNHfW6ldHnvckBie3OjeR?= NFm5UnYzOCEQvF2= MULEUXNQ Ml\O[IVkemWjc3XzJHBUSSC|ZXPy[ZRqd25iYX7kJJA3PSCneIDy[ZN{cW:wIHzleoVtew>? MmLaNlE4ODlzM{C=
Kasumi-1 MoXoS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NUPyfVV1hjVyIN88US=> NInBemZFVVOR NW\rU3hHcW6qaXLpeJMh[2WubDDwdo9tcW[ncnH0bY9v NFX3fY8zOzN7MEWzOi=>
SKNO-1 MUHHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NEHu[Vd,PTBizszN NXn2dHFZTE2VTx?= MmjGbY5pcWKrdIOgZ4VtdCCycn;sbYZmemG2aX;u NEXxW5QzOzN7MEWzOi=>
Kasumi-1 NGXrb2JMcW6jc3WgZZN{[Xl? NGf3SFJ,OTBizszN NFnSVFZFVVOR MnHNdoVlfWOnczDlfJBz\XO|aX;uJI9nKGGlZYT5cIF1\WRiaHnzeI9v\SCKMz|CpIMuc2m2wrDhcoTDqGKlbD2y M4fnOFI{OzlyNUO2
SKNO-1 NXi1UVB4U2mwYYPlJIF{e2G7 M4myPZ4yOCEQvF2= NFv4dWhFVVOR Mo\IdoVlfWOnczDlfJBz\XO|aX;uJI9nKGGlZYT5cIF1\WRiaHnzeI9v\SCKMz|CpIMuc2m2wrDhcoTDqGKlbD2y NGn5eIQzOzN7MEWzOi=>
A549 NEHtXGxHfW6ldHnvckBie3OjeR?= NYLEWXk{OTBizszN NH\wVYZFVVOR NEXQTJdmdmijbnPld{BucXSxdHnjJINifGG|dILvdIhm MWmyOFc1PjV5NB?=
NRK-52E MY\GeY5kfGmxbjDhd5NigQ>? NYnsU49oOTBizszN Mnj5SG1UVw>? M3:wT4lvcGmkaYTzJGFv\yCLST3pcoR2[2WmIGPURXQ{KG63Y3zlZZIhfHKjboPsc4NifGmxbjDhcoQhfGinIHX4dJJme3Orb36gc4YhXEeILd8yNUwh[2:ubHHn[Y4hUVZiYX7kJIZq[nKxbnXjeIlv NFfUN2gzPTB6OECwNi=>
PC12 MV3Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NWi1UXNthjF{LkWg{txO MlzXSG1UVw>? MlfsdJJmfmWwdIOgWHNCNWmwZIXj[YQhdmW3cnn0[UBnd3KvYYTpc44> MnTtNlUyOjh|OE[=
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A549 NYP0dpZ1TnWwY4Tpc44h[XO|YYm= NIrOTo1,PTBizszN M2TkTWROW09? M1rDeoFn\mWldIOgeIhmKH[rcnHsJIxq\mViY4njcIUh[W6mIHjvd5QhemW|cH;ud4U> MWCyOlcyOTd2OB?=
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... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
cMET / p-cMET / p-AKT / p-ERK / p-rpS6 ; 

PubMed: 23022995     


A498 and 769P cell lines were treated with increasing concentrations of ARQ 197 for 24 h. Total c-Met expression remained relatively stable with drug treatment. Phosphorylated c-Met expression was highest in control (untreated cells) and was blocked with increasing concentrations of ARQ 197. Downstream changes in the c-Met pathway were seen predominantly in phosphorylated AKT, while decreased phosphorylated ERK1/2 and phosphorylated rpS6 (P70S6Kinase) occurred at higher c-Met inhibitor concentrations.

23022995
Growth inhibition assay
Cell viability; 

PubMed: 23598276     


Cells were treated with the increasing concentrations of tivantinib for 72 hr. Viable cells were assessed by CellTiter-Glo assay and were graphed relative to untreated cells. Experiments were carried out in sextuplet. The average values and SDs are shown. 

23598276
In vivo 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]

Protocol

Kinase Assay:[1]
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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.
Cell Research:[1]
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  • Cell lines: T29, MKN-45 and MDA-MB-231 cells
  • Concentrations: 0.03-10 μM
  • Incubation Time: 24, 32, and 48 hours
  • Method: 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.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female athymic nude mice bearing HT29, MKN-45, or MDA-MB-231 tumor xenografts
  • Dosages: 200 mg/kg
  • Administration: Orally administered
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 73 mg/mL (197.6 mM)
Water Insoluble
Ethanol 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.

Chemical Information

Molecular Weight 369.42
Formula

C23H19N3O2

CAS No. 905854-02-6
Storage powder
in solvent
Synonyms N/A
Smiles C1CC2=C3C(=CC=C2)C(=CN3C1)C4C(C(=O)NC4=O)C5=CNC6=CC=CC=C65

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02150733 Completed Drug: Tivantinib Hepatic Impairment|Solid Tumor|Cancer Daiichi Sankyo Inc.|Medpace Inc. April 2014 Phase 1
NCT01892527 Unknown status Drug: Tivantinib (ARQ197) Colorectal Cancer Metastatic|C-met Overexpression Armando Santoro MD|Istituto Clinico Humanitas March 2013 Phase 2
NCT02049060 Completed Drug: Tivantinib Malignant Pleural Mesothelioma|Nonsquamous Nonsmall Cell Neoplasm of Lung Armando Santoro MD|Istituto Clinico Humanitas January 2013 Phase 1|Phase 2
NCT01755767 Completed Drug: Tivantinib|Drug: Placebo Hepatocellular Carcinoma Daiichi Sankyo Inc.|ArQule Inc. (a wholly owned subsidiary of Merck Sharp and Dohme a subsidiary of Merck & Co. Inc.) December 27 2012 Phase 3

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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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.

c-Met Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID