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Tivantinib (ARQ 197)

Name: Tivantinib (ARQ 197)
Brand: Selleck Chemicals
SKU: S2753
Rating: 5 (37 reviews)

Catalog No.S2753

For research use only.

Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with K_i 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.

CAS No. 905854-02-6

Selleck's Tivantinib (ARQ 197) has been cited by 37 publications

Purity & Quality Control

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c-Met Signaling Pathway Map

Biological Activity

Description

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 K_m of ATP, exposure of c-Met to 0.5 μM ARQ-197 decreased the V_max of c-Met by approximately 3-fold. The ability of ARQ-197 to decrease the V_max 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 K_i 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	M1zue2tqdmG\|ZTDhd5NigQ>?	MXT+NVAh\|ryP		NHTDPWtqdmirYnn0d{BkNU2ndDDwbI9{eGixconsZZRqd25iYX7kJIRwf26\|dILlZY0h[y2PZYSgd4lodmGuaX7nJJBifGi5YYnz	MWmyNFQ5PDBzOB?=
HT29	NHG4XnFMcW6jc3WgZZN{[Xl?	NVXIfZFIhjFyIN88US=>		M{\nRYlvcGmkaYTzJIMuVWW2IIDoc5NxcG:{eXzheIlwdiCjbnSg[I94dnO2cnXhcUBkNU2ndDDzbYdv[WyrbnegdIF1cHejeYO=	NU\xZWRMOjB2OESwNVg>
MDA-MB-231	NUTZSnBDU2mwYYPlJIF{e2G7	MWL+NVAh\|ryP		MoC1bY5pcWKrdIOgZ{1O\XRicHjvd5Bpd3K7bHH0bY9vKGGwZDDkc5dve3S{ZXHtJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7cx?=	MV6yNFQ5PDBzOB?=
NCI-H441	M2frSWtqdmG\|ZTDhd5NigQ>?	MWj+NVAh\|ryP		M1TEfYlvcGmkaYTzJIMuVWW2IIDoc5NxcG:{eXzheIlwdiCjbnSg[I94dnO2cnXhcUBkNU2ndDDzbYdv[WyrbnegdIF1cHejeYO=	MnPSNlA1QDRyMUi=
SK-MEL-28	MljvS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	M2OxPVM{KM7:TR?=		M1K1ZmlEPTB-M{Og{txO	MYmyNFQ5PDBzOB?=
NCI-H661	MnvBS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	NEH1fVM{OyEQvF2=		MnjlTWM2OD5\|MzFOwG0>	NY\XOIIzOjB2OESwNVg>
NCI-H446	MUnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M4nLU\|M{KM7:TR?=		MlzWTWM2OD15IN88US=>	MX6yNFQ5PDBzOB?=
MDA-MB-231	NIrxblhIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M4X1OFM{KM7:TR?=		M3TUbGlEPTB;MD61OUDPxE1?	MlLUNlA1QDRyMUi=
DLD-1	NVf5flhOT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NEfBTVE{OyEQvF2=		MVrJR\|UxRTBwNUOg{txO	M3eyNVIxPDh2MEG4
A549	NYPPOVhmT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	M{fCbVM{KM7:TR?=		MYrJR\|UxRTBwNUmg{txO	NVO1WZo6OjB2OESwNVg>
SK-OV-3	Ml\PS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	M33FdlM{KM7:TR?=		NHzyTGNKSzVyPUCuOlYh\|ryP	M2\BeVIxPDh2MEG4
NCI-H460	NUf2fnB1T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MVSzN{DPxE1?		NVnVSotIUUN3ME2wMlYh\|ryP	M2LVWVIxPDh2MEG4
A375	NGe2UXpIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NVm5e4lmOzNizszN		NVfPOFBNUUN3ME2wMlQzKM7:TR?=	MojlNlA1QDRyMUi=
NCI-H441	NWG0XJpRT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MUCzN{DPxE1?		M3TjZWlEPTB;MD6zJO69VQ>?	NYr2THpbOjB2OESwNVg>
HT29	MVLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	MYqzN{DPxE1?		MlnyTWM2OD1yLkS5JO69VQ>?	NGH5VI8zODR6NECxPC=>
MKN-45	MUDHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	NF\qOno{OyEQvF2=		M1jmbmlEPTB;MD61PEDPxE1?	MmW3NlA1QDRyMUi=
HT29	MXzBdI9xfG:\|aYOgZZN{[Xl?	M1n2bp4yOCEQvF2=		NIixO2p{cWewaX\pZ4FvfGy7IHnu[JVk\XNiYYDvdJRwe2m\|IHL5JFgxNTlyJT6=	M3Xo[FIxPDh2MEG4
MKN-45	NFz4O2dCeG:ydH;zbZMh[XO\|YYm=	MkXJglExKM7:TR?=		NH;GXnR{cWewaX\pZ4FvfGy7IHnu[JVk\XNiYYDvdJRwe2m\|IHL5JFgxNTlyJT6=	NVW2OJZnOjB2OESwNVg>
MDA-MB-231	Mn\jRZBweHSxc3nzJIF{e2G7	NF[2dYF,OTBizszN		M3q3WI1w\GW\|dHz5JIlv\HWlZYOgZZBweHSxc3nzJIJ6KDN3JT6=	M1exeVIxPDh2MEG4
MDA-MB-231/TGL	M{\5W2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MkXyglExOCEQvF2=		MX7HTVUxRTFwMjFOwG0>	NFvaNVEzOjB{N{[5NC=>
1833/TGL	Ml\LS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	Ml3PglExOCEQvF2=		M4fzTGdKPTB;Mz63JO69VQ>?	M17leFIzODJ5Nkmw
EBC1	M{T6XGN6fG:2b4jpZ:Kh[XO\|YYm=	M1jObp4yOCEQvF2=		MVrpcohq[mm2czD0bIUh[2WubDDndo94fGhw	MYGyN\|U6QDJ5Nh?=
SNU638	NF3WWI5EgXSxdH;4bYPDqGG\|c3H5	MWn+NVAh\|ryP		MVHpcohq[mm2czD0bIUh[2WubDDndo94fGhw	MnvINlM2QTh{N{[=
A549	MXfDfZRwfG:6aXRCpIF{e2G7	MnvYglExKM7:TR?=		NFPQT5Bvd3RiYX\m[YN1	MW[yN\|U6QDJ5Nh?=
H460	NYjtZWxbS3m2b4TvfIlkyqCjc4PhfS=>	NW[wR3VLhjFyIN88US=>		Mnvkco91KGGoZnXjeC=>	MVmyN\|U6QDJ5Nh?=
HCC827	Mk\CR5l1d3SxeHnjxsBie3OjeR?=	MVX+NVAh\|ryP		NYX2TWdkdm:2IHHm[oVkfA>?	NU[4bYhbOjN3OUiyO\|Y>
A549	MmLzSpVv[3Srb36gZZN{[Xl?	NUiwNpBGOTBizszN		MWXkbZNzfXC2czDtbYNzd3S3YoXs[S=>	NH[2VJozOzV7OEK3Oi=>
EBC1	MVLGeY5kfGmxbjDhd5NigQ>?	M2D6SFExKM7:TR?=		NGP2XZVlcXO{dYD0d{BucWO{b4T1ZpVt\Q>?	MYWyN\|U6QDJ5Nh?=
H460	Mn;ySpVv[3Srb36gZZN{[Xl?	MlL5NVAh\|ryP		M4\Vd4lvcGmkaYTzJJR2[nWuaX6gdI9tgW2ncnn6ZZRqd25?	NEDEU4kzPTNzM{CxNC=>
K562/VCR	MluyR5l1d3SxeHnjxsBie3OjeR?=	NHzDW3h,OTBizszN		M1nSZ5Npd3e\|IHP5eI91d3irYzDhZ5Rqfmm2eR?=	MmDPNlU{OTNyMUC=
CEM/VBL	Mk\WR5l1d3SxeHnjxsBie3OjeR?=	M2rFWp4yOCEQvF2=		M4TROZNpd3e\|IHP5eI91d3irYzDhZ5Rqfmm2eR?=	NFHJcVMzPTNzM{CxNC=>
U266	M1fYTGN6fG:2b4jpZ:Kh[XO\|YYm=	NYDGNGZThjNizszNxsA>		NUHpZ4pbUUN3ME2xMlEh\|ryP	M3zUdVI2QDFyMEGz
OPM-2	NXTXenpwS3m2b4TvfIlkyqCjc4PhfS=>	MnXqglMh\|ryPwrC=		MVjJR\|UxRTFwODFOwG0>	NUHJcGVIOjV6MUCwNVM>
MM.1S	MXrDfZRwfG:6aXRCpIF{e2G7	M3PXfp4{KM7:TdMg		NFfuZ4hKSzVyPUGuOkDPxE1?	M3fnRVI2QDFyMEGz
MM.1R	MV7Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	MmHDN{DPxE4EoB?=		Mlq1bY5pcWKrdIOgZ4VtdCCpcn;3eIgh[nliNEml	MV6yOVgyODBzMx?=
RPMI-8226	MVzDfZRwfG:6aXRCpIF{e2G7	M4K0UZ4{KM7:TdMg		NGTqe3dKSzVyPUCuPUDPxE1?	NFHQVpgzPThzMECxNy=>
ANBL-6	NFrx[45EgXSxdH;4bYPDqGG\|c3H5	NVi5eIpLOSEQvF5CpC=>		M3G0WIlv\HWlZYOgZ4VtdCCmZXH0bEBjgSCvb4LlJJRp[W5iNUCl	NETTfJkzPThzMECxNy=>
ANLB-6/V10R	NXrlNWNGS3m2b4TvfIlkyqCjc4PhfS=>	NHOzWVcyKM7:TdMg		MXXpcoR2[2W\|IHPlcIwh\GWjdHigZpkhdW:{ZTD0bIFvKDVyJR?=	NGjMO5EzPThzMECxNy=>
KAS-6/1	MkfGR5l1d3SxeHnjxsBie3OjeR?=	MYGxJO69VcLi		MX\pcoR2[2W\|IHPlcIwh\GWjdHigZpkhdW:{ZTD0bIFvKDVyJR?=	NWnpeos6OjV6MUCwNVM>
KAS-6/V10R	M3nDW2N6fG:2b4jpZ:Kh[XO\|YYm=	MYqxJO69VcLi		NFe1SW5qdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=>	NF3EOnkzPThzMECxNy=>
KAS-6/R10R	NGnJfnNEgXSxdH;4bYPDqGG\|c3H5	MnPuNUDPxE4EoB?=		NH;JbnZqdmS3Y3XzJINmdGxiZHXheIgh[nlibX;y[UB1cGGwIEWwKS=>	MkfxNlU5OTByMUO=
8226/S	NISxc\|NIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NGDObng{KM7:TdMg		NX;SOmpbcW6qaXLpeJMh[2WubDDndo94fGhiYomgOVQm	MoCwNlU5OTByMUO=
8226/LR-5	M3LVTWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NXLl[pdwOyEQvF5CpC=>		Ml\zbY5pcWKrdIOgZ4VtdCCpcn;3eIgh[nliNUSl	MUKyOVgyODBzMx?=
Huh7	NXK0U\|RGS3m2b4TvfIlkyqCjc4PhfS=>	M{TaVp41NjhizszNxsA>	MlvDSG1UVw>?	MoW2TWM2OD17Lkmgcm0>	MmrZNlYzPTl{NUC=
Hep3B	MWXDfZRwfG:6aXRCpIF{e2G7	NYrk[lVohjRwODFOwG3DqA>?	M2X3PGROW09?	Mlq3TWM2OD12NEiuO{BvVQ>?	NXHLPVdUOjZ{NUmyOVA>
HepG2	MYTDfZRwfG:6aXRCpIF{e2G7	MkXhglQvQCEQvF5CpC=>	NV7FfHJVTE2VTx?=	NEHvOVFKSzVyPUGzPU44PyCwTR?=	NH\YOoczPjJ3OUK1NC=>
Chang	MmPQR5l1d3SxeHnjxsBie3OjeR?=	Ml7lglQvQCEQvF5CpC=>	M3;zUGROW09?	MVzJR\|UxRTR2OD63JI5O	MoPMNlYzPTl{NUC=
Huh7	NFnNeI5HfW6ldHnvckBie3OjeR?=	M3z4WlEvPiEQvF5CpC=>	NHz4b\|VFVVOR	MmnKZ4F2e2W\|IHGgS\|IwVSClZXzsJIN6[2ynIHHydoV{fA>?	NEeyRmkzPjJ3OUK1NC=>
Hep3B	NIHQc3lHfW6ldHnvckBie3OjeR?=	MYSxMlYh\|ryPwrC=	M3PJWWROW09?	MlH6Z4F2e2W\|IHGgS\|IwVSClZXzsJIN6[2ynIHHydoV{fA>?	MVGyOlI2QTJ3MB?=
HepG2	NF7MS3hHfW6ldHnvckBie3OjeR?=	NIW1TpcyNjZizszNxsA>	MlvwSG1UVw>?	M1jWb4NifXOnczDhJGczN01iY3XscEBkgWOuZTDhdpJme3R?	MW[yOlI2QTJ3MB?=
Chang	MYjGeY5kfGmxbjDhd5NigQ>?	NGTj[\|kyNjZizszNxsA>	M3fQTmROW09?	M3jQ[INifXOnczDhJGczN01iY3XscEBkgWOuZTDhdpJme3R?	NUS3PYVyOjZ{NUmyOVA>
MHCC97L	NH\uW4pIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	MWn+NVAh\|ryP	MnrMSG1UVw>?	NWjyNng2UUN3ME2zNVUhdk1?	NF;zTHIzPjR3OEm1Ny=>
MHCC97H	M2XKcGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	M1nneZ4yOCEQvF2=	NGC1TnNFVVOR	MWXJR\|UxRTN4OPMAjUBvVQ>?	MkH5NlY1PTh7NUO=
Huh7	MoT3S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	MVj+NVAh\|ryP	NWDufHlrTE2VTx?=	NYXa[2kzUUN3ME2yOlUhdk1?	Mo\FNlY1PTh7NUO=
HepG2	NHW2bplIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M2\GW54yOCEQvF2=	M3HtRWROW09?	M1vsb2lEPTB;M{myJI5O	NFrXUXczPjR3OEm1Ny=>
MHCC97L	MX3GeY5kfGmxbjDhd5NigQ>?	Mnq4NUDPxE4EoB?=	NYrTNJN1TE2VTx?=	NYjyboUzcW6mdXPld{BucWO{b4T1ZpVt\XNiZHXwc4x6dWW{aYrheIlwdg>?	MYWyOlQ2QDl3Mx?=
Huh7	M132R2Z2dmO2aX;uJIF{e2G7	M2nZNFEh\|ryPwrC=	NGGwbFZFVVOR	MnO3bY5lfWOnczDtbYNzd3S3YoXs[ZMh\GWyb3z5cYVzcXqjdHnvci=>	M4i1TVI3PDV6OUWz
MHCC97L	NE\qTmFCeG:ydH;zbZMh[XO\|YYm=	M2XjTVEh\|ryPwrC=	MkHCSG1UVw>?	MYHpcoR2[2W\|IHHwc5B1d3Orcx?=	M2rOOVI3PDV6OUWz
Huh7	M1\SNWFxd3C2b4Ppd{Bie3OjeR?=	MVixJO69VcLi	Mn7LSG1UVw>?	MVvpcoR2[2W\|IHHwc5B1d3Orcx?=	NUPEdGpGOjZ2NUi5OVM>
C3H 10T1/2 mouse fibroblasts	M3WwNmtqdmG\|ZTDhd5NigQ>?	Mn:zNlUh\|ryP	MVHEUXNQ	MVry[YR2[2W\|IFjpd5RwdmViSEOgZY5lKEh2IHHj[ZR6dGG2aX;uJIxmfmWuc9Mg	Ml;lNlA2OzR\|NEW=
H23	NU[3c\|V4T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NEjGfnIzPSEQvF2=	MVTEUXNQ	M3XMXpNq\26rZnnjZY51dHliaX7obYJqfHNiY3XscEBoem:5dHiu	MkXzNlA2OzR\|NEW=
WM35	M3nPSGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NXPVZ3d2OTBizszN	MX3EUXNQ	MU\zbYdvcW[rY3HueIx6KGmwaHnibZR{KGOnbHyg[5Jwf3SqLh?=	MYSyNFU{PDN2NR?=
NIH 3T3	NFrYTmlIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NEX1XFEyOCEQvF2=	MX\EUXNQ	MkTa[I9meyCwb4SgbIF3\SCjIIPp[45q\mmlYX70JIlvcGmkaYTvdpkh\W[oZXP0	NGm1[WIzODV\|NEO0OS=>
H838	MoL6S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	MXyxNEDPxE1?	NHPVZ2JFVVOR	MUDkc4V{KG6xdDDoZZZmKGFic3nncolncWOjboSgbY5pcWKrdH;yfUBm\m[nY4S=	NV[1XFd2OjB3M{SzOFU>
H1395	MUTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	NUXIbnJ[OTBizszN	NYq3fIJ1TE2VTx?=	MWTkc4V{KG6xdDDoZZZmKGFic3nncolncWOjboSgbY5pcWKrdH;yfUBm\m[nY4S=	MU[yNFU{PDN2NR?=
Quiescent S2	Mn\RT4lv[XOnIHHzd4F6	M4\6bFMxKM7:TR?=	NYqwfopbTE2VTx?=	M{noZYNwdXCuZYTlcJkh[WK{b3fheIV{KFSVQT3pcoR2[2WmIHj5dIVz[WOndInsZZRqd25ib3[gTFNMPG2nMzDobZN1d26ncx?=	NH74TGEzOTVzOEmxOS=>
PC3	M{TOO2Fxd3C2b4Ppd{Bie3OjeR?=	M17TW\|IxKM7:TR?=	M{D4emROW09?	MorwbY5lfWOnczDhdI9xfG:\|aYO=	NWDHbo9TOjF5MEmxN\|A>
Du145	MUPBdI9xfG:\|aYOgZZN{[Xl?	NHLLOoEzOCEQvF2=	MYHEUXNQ	MkL0bY5lfWOnczDhdI9xfG:\|aYO=	NHrCenczOTdyOUGzNC=>
LNCaP	M322V2Fxd3C2b4Ppd{Bie3OjeR?=	MXGyNEDPxE1?	MX7EUXNQ	MWnpcoR2[2W\|IHHwc5B1d3Orcx?=	NXKydW5KOjF5MEmxN\|A>
LAPC-4	MWrBdI9xfG:\|aYOgZZN{[Xl?	NETYRZMzOCEQvF2=	NVLEUVRHTE2VTx?=	NFm3TlRqdmS3Y3XzJIFxd3C2b4Ppdy=>	MX[yNVcxQTF\|MB?=
LNCaP	NFXreHpHfW6ldHnvckBie3OjeR?=	MXyyNEDPxE1?	NHi3TVdFVVOR	M{iwToRm[3KnYYPld{BRW0Fic3XjdoV1cW:wIHHu[EBxPjViZYjwdoV{e2mxbjDs[ZZmdHN?	NWGyeWppOjF5MEmxN\|A>
LAPC-4	M4eyR2Z2dmO2aX;uJIF{e2G7	NUi0V5lNOjBizszN	NHTZeVVFVVOR	MmPj[IVkemWjc3XzJHBUSSC\|ZXPy[ZRqd25iYX7kJJA3PSCneIDy[ZN{cW:wIHzleoVtew>?	M1XXT\|IyPzB7MUOw
Kasumi-1	MWrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	NHfCfJd,PTBizszN	M2rCfWROW09?	MXXpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36=	MlzsNlM{QTB3M{[=
SKNO-1	NGr6OnhIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NIn3TpJ,PTBizszN	NFH1eIhFVVOR	MUXpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36=	M{\l[VI{OzlyNUO2
Kasumi-1	M4jZbmtqdmG\|ZTDhd5NigQ>?	MYT+NVAh\|ryP	NH;TOY5FVVOR	NF\EbYJz\WS3Y3XzJIV5eHKnc4Ppc44hd2ZiYXPleJlt[XSnZDDobZN1d26nIFizMOKh[y2taYVCpIFv\MLiYnPsMVI>	NHqx[YEzOzN7MEWzOi=>
SKNO-1	MXfLbY5ie2ViYYPzZZk>	MYD+NVAh\|ryP	MmLsSG1UVw>?	NEPC[3Fz\WS3Y3XzJIV5eHKnc4Ppc44hd2ZiYXPleJlt[XSnZDDobZN1d26nIFizMOKh[y2taYVCpIFv\MLiYnPsMVI>	MVyyN\|M6ODV\|Nh?=
A549	NWHRTHhKTnWwY4Tpc44h[XO\|YYm=	MXexNEDPxE1?	MUXEUXNQ	M{LTOIVvcGGwY3XzJI1qfG:2aXOgZ4F1[XO2cn;wbIU>	MmLsNlQ4PDZ3N{S=
NRK-52E	MofzSpVv[3Srb36gZZN{[Xl?	M3i1flExKM7:TR?=	MkHESG1UVw>?	Ml\EbY5pcWKrdIOgRY5oKEmLLXnu[JVk\WRiU2TBWFMhdnWlbHXhdkB1emGwc3zvZ4F1cW:wIHHu[EB1cGViZYjwdoV{e2mxbjDv[kBVT0ZvzsKxMEBkd2yuYXflckBKXiCjbnSg[oljem:wZXP0bY4>	M{m0R\|I2ODh6MECy
PC12	M3r5Omdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MlTMglEzNjVizszN	MmrQSG1UVw>?	NF2zUYxxemW4ZX70d{BVW0FvaX7keYNm\CCwZYXybZRmKG[xcn3heIlwdg>?	NYfRO\|dCOjVzMkizPFY>
HPMCs	NXnJXoIyTnWwY4Tpc44h[XO\|YYm=			NHPle5Jz\X[ncoPld{BmeGm2aHXsbYFtKHSxIH3ld4Vv[2i7bXHsJJRz[W6\|aYTpc44hd2ZiaIXtZY4heGW{aYTvcoVidCCvZYPveIhmdGmjbDDj[Yxtew>?	MljtNlYxPDV5OEC=
A549	MV3GeY5kfGmxbjDhd5NigQ>?	MmjDglUxKM7:TR?=	NFfyfIpFVVOR	MorFZYZn\WO2czD0bIUhfmm{YXygcIln\SCleXPs[UBidmRiaH;zeEBz\XOyb37z[S=>	NYPNU\|dyOjZ5MUG3OFg>
RAW264.7	NHvacYRHfW6ldHnvckBie3OjeR?=	NWXxSoc6hjNyIN88US=>	NGi5bFZFVVOR	MkX2doVlfWOnczDwdo8ucW6obHHtcYF1d3K7IHflcoUh\XiycnXzd4lwdg>?	MUiyOlcyQDV6Nh?=
MEMM	MX7LbY5ie2ViYYPzZZk>	MmjoNVUhyrWP	NWPiOmxPTE2VTx?=	NEnwS4hl\WO{ZXHz[ZMh[WOndInsZZRqd25ib3[gbIl{fG:wZTDINy=>	Mm\xNlY6OjF3ME[=
MEMM	MVTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	NIPQU4V,OjBiwsXN	MX\EUXNQ	MUTpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36=	M1\VNFI3QTJzNUC2
MEMM	MoXhRZBweHSxc3nzJIF{e2G7	NYTodpB7OTViwsXN	NHvBdWxFVVOR	NHnrboxqdmS3Y3XzJJRp\SCycnXz[Y5k\SCxZjD0bIUh[XCxcITvd4l{KHC{b4TlbY4tKGOuZXH2[YQhS2G\|cHHz[U0{	MnXWNlY6OjF3ME[=
T47D	NUXzWZFFT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MUGxNEDPxE1?	M3;WbGROW09?	NY[xb2FlUUN3ME23NkBvVQ>?	NFnyU5YyQDN6MUS0OC=>
ZR-75-1	NGDSNo1Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NWnBTIhIOTBizszN	NWLUbZdUTE2VTx?=	NGPnWFBKSzVyPUe5JI5O	NV\E[5VuOTh\|OEG0OFQ>
BT474	MlTYS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	MlPINVAh\|ryP	NF[4SnhFVVOR	M{XBemlEPTB;OE[gcm0>	MonGNVg{QDF2NES=
HCC1954	NWXLSVg5T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NXjhfmpzOTBizszN	NWDRNpRHTE2VTx?=	NH7HPWhKSzVyPUGxPUBvVQ>?	NVnUXWh1OTh\|OEG0OFQ>
MDA-MB-453	NFvVdpNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	MmrONVAh\|ryP	NVLkb3NnTE2VTx?=	NHXUeVNKSzVyPUm3OUBvVQ>?	MVGxPFM5OTR2NB?=
MDA-MB-468	MlHSS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	NY\tNYpFOTBizszN	NI\KWlFFVVOR	M13hcGlEPTB;M{KwPEBvVQ>?	Mn7tNVg{QDF2NES=
SkBr3	NYnJfZF5T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NYWwW5BWOTBizszN	Mm[5SG1UVw>?	NXvseI42UUN3ME6xNEwxODBibl2=	MoTwNVg{QDF2NES=
MDA-MB-231	NXrHeJNuT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MWOxNEDPxE1?	M3PlR2ROW09?	NWO0[HJCUUN3ME6xNEwxODBibl2=	NEXPNIoyQDN6MUS0OC=>
HCT116	M{\OZWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NY\CfHR4OTBizszN	MlTmSG1UVw>?	NELDSYpKSzVyPUW4N\|Yhdk1?	M3vhU\|E5OzhzNES0
HT29	M1ftcWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	Mn3zNVAh\|ryP	NYSzTlJSTE2VTx?=	M{LIeGlEPTB-MUCsNFAxKG6P	NILaPIYyQDN6MUS0OC=>
HFF	MYTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M4HwPFExKM7:TR?=	M2jC[mROW09?	M3Wwd2lEPTB;N{[xOUBvVQ>?	MnHiNVg{QDF2NES=
HN5	MoDaS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	M1f6SVExKM7:TR?=	NFjn[oZFVVOR	MWjJR\|UxRjFyLECwNEBvVQ>?	NUXX[FJ5OTh\|OEG0OFQ>
786-0	NUjVepVzT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MnHoNVAh\|ryP	NIfUd2VFVVOR	NXzwUYlDUUN3ME20NFA6KG6P	Ml7QNVg{QDF2NES=
H157	M3\XRWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NFXsbGIyOCEQvF2=	MnXuSG1UVw>?	M2HJVGlEPTB;Mk[0NkBvVQ>?	MYixPFM5OTR2NB?=
NCI-H460	NXzMWJFvT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MorYNVAh\|ryP	M1nkfGROW09?	NH7wWpBKSzVyPkKsOVAxKG6P	MnHGNVg{QDF2NES=
SKOV-3	M{fBSmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MVixNEDPxE1?	M1u3TWROW09?	NF7iUIZKSzVyPUKxNlYhdk1?	MWqxPFM5OTR2NB?=
OVCAR-3	NYHCWXpoT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NGLMXlAyOCEQvF2=	NV3WTG5oTE2VTx?=	MoHiTWM2OD1{OUG4JI5O	MWexPFM5OTR2NB?=
BXPC3	NXr4dZVoT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	M4S4PFExKM7:TR?=	NHnST4pFVVOR	NYHJZW1oUUN3ME2zNVQyKG6P	MmHyNVg{QDF2NES=
MiaPaCa	M{e3S2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NWWybII1OTBizszN	M4LKXmROW09?	NEHoO25KSzVyPUW0N\|Mhdk1?	NGGxfmwyQDN6MUS0OC=>
PANC-1	NInTdnVIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M{jMfVExKM7:TR?=	M2KycmROW09?	NI\QTIdKSzVyPUi2PFEhdk1?	MmnvNVg{QDF2NES=
LNCaP	MVjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	NY\pbpJEOTBizszN	NHLLbJRFVVOR	M{H2bWlEPTB;MUS3JI5O	NV;E[WZ3OTh\|OEG0OFQ>
DU145	NF;kRXFIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NIrZeWgyOCEQvF2=	MWLEUXNQ	NYK2OY9QUUN3ME2zPFEzKG6P	NGXvZ48yQDN6MUS0OC=>
PC3	NHv2XpNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NWDHWlZ2OTBizszN	M1\m[mROW09?	MVLJR\|UxRjFyLECwNEBvVQ>?	M1nhUVE5OzhzNES0
BT474	M2LNZmtqdmG\|ZTDhd5NigQ>?	NUO0PFhiOTBizszN	M{n6ZmROW09?	M3jBZolvcGmkaYTzJJBIW0t\|zsKge4l1cCCLQ{WwJI9nKDF4MDDuUS=>	MlW3NVg{QDF2NES=
786-0	M4LFbWtqdmG\|ZTDhd5NigQ>?	M4XvclExKM7:TR?=	NFXXR\|lFVVOR	NWroO3VOcW6qaXLpeJMheEeVS{ROtkB4cXSqIFnDOVAhd2ZiMUWwJI5O	MWKxPFM5OTR2NB?=
LNCaP	Mnr2T4lv[XOnIHHzd4F6	MYqxNEDPxE1?	MVTEUXNQ	NETC[mRqdmirYnn0d{BxT1ONM98yJJdqfGhiSVO1NEBw\iB2MzDuUS=>	MnXUNVg{QDF2NES=
PC3	NVfhcXdGU2mwYYPlJIF{e2G7	NFzQW20yOCEQvF2=	MnqwSG1UVw>?	NEXIXFRqdmirYnn0d{BxT1ONM98yJJdqfGhiSVO1NEBw\iB2OTDuUS=>	NIfjeHUyQDN6MUS0OC=>
KARPAS-231	M3zhSmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	M3nEVlExKM7:TR?=	NHPXdVhFVVOR	NEn6[nJGSzVyPUSxJI5O	MVOxPVA3PDd\|MB?=
CCRFSB	NWLWdIw2T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NGPqS\|UyOCEQvF2=	NW\2ToFvTE2VTx?=	NGWz[GFGSzVyPUG1OUBvVQ>?	MmLaNVkxPjR5M{C=
SUP B15	NVLYR3pOT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	Mm[5NVAh\|ryP	MmXPSG1UVw>?	NELvc3FGSzVyPUG5O{BvVQ>?	MUexPVA3PDd\|MB?=
SD-1	NV\kZYFqT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MoPDNVAh\|ryP	MmDNSG1UVw>?	MnvFSWM2OD1\|MkCgcm0>	NGn6UG8yQTB4NEezNC=>
RS4;11	NE\sTnRIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	Ml3KNVAh\|ryP	NWTlN\|l4TE2VTx?=	M3;mUmVEPTB;NkW0JI5O	Mn3vNVkxPjR5M{C=
MN-60	NEjyWoNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M3THflExKM7:TR?=	NHW0NpNFVVOR	NVLURpFHTUN3ME2zOlAzKG6P	MlzONVkxPjR5M{C=
Tanoue	NVvSTGpET3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	Mm\YNVAh\|ryP	MUTEUXNQ	Ml3TSWM2OD12NUG3JI5O	NYixU4hnOTlyNkS3N\|A>
RCH-ACV	NWD0fXFxT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	M1;aTVExKM7:TR?=	M2HpW2ROW09?	NEPidItGSzVyPUG1NkBvVQ>?	MV6xPVA3PDd\|MB?=
SEM	MVrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	MVGxNEDPxE1?	MnG2SG1UVw>?	NX7mZ3N[TUN3ME2yNFIhdk1?	NECwcZYyQTB4NEezNC=>
KASUMI-2	M1Tt[mdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NHX5NGgyOCEQvF2=	NXvDN3NETE2VTx?=	M1K1cWVEPTB;MkK1JI5O	MXyxPVA3PDd\|MB?=
REH	MVfHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M1PjPFExKM7:TR?=	MlLKSG1UVw>?	Mm\LSWM2OD1{OEigcm0>	NFOxeXMyQTB4NEezNC=>
697	MoL0S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	MUixNEDPxE1?	NYXNN5Q4TE2VTx?=	MW\FR\|UxRTN\|ODDuUS=>	NIjEeFUyQTB4NEezNC=>
NALM-6	MkDpS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	NGTJeZcyOCEQvF2=	NEjSO29FVVOR	M{m0NWVEPTB;NEKxJI5O	NVO2b486OTlyNkS3N\|A>
MHH-CALL–3	M3Lt[mdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	Mln6NVAh\|ryP	M{\0d2ROW09?	MkHGSWM2OD16MUKgcm0>	MVWxPVA3PDd\|MB?=
MHH-CALL–2	MlO4S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	NWrFSXVYOTBizszN	M3m1dGROW09?	NXPoZYsyTUN3ME2yNVE1KG6P	NH;zZVEyQTB4NEezNC=>
J.GAMMA-1	NEDvUW5Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M2\3blExKM7:TR?=	M1XBVmROW09?	MorqSWM2OD14NTDuUS=>	MkDFNVkxPjR5M{C=
JR45.01	NFKxboZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M2LoeFExKM7:TR?=	M2rGcmROW09?	MVTFR\|UxRTZ6IH7N	NIDrVWwyQTB4NEezNC=>
A3	NXvnOItTT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MonMNVAh\|ryP	NXLRblU1TE2VTx?=	M2[xZmVEPTB;Nkmgcm0>	M1TjclE6ODZ2N{Ow
I 2.1	NInDWVVIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NI\vVYUyOCEQvF2=	NUfQTFFLTE2VTx?=	M3j0Z2VEPTB;N{Ogcm0>	M3Lx[FE6ODZ2N{Ow
MOLT-3	NFvBTopIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M4G2blExKM7:TR?=	MkH6SG1UVw>?	M1W4R2VEPTB;N{Sgcm0>	Mk\ONVkxPjR5M{C=
P116	NGPpR2ZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	MonRNVAh\|ryP	M{P6N2ROW09?	MkTCSWM2OD15ODDuUS=>	NVTETJB5OTlyNkS3N\|A>
J.Cam1.6	NWnKbYhsT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MX[xNEDPxE1?	NX\RU4xJTE2VTx?=	M2jX[GVEPTB;N{mgcm0>	M4e5R\|E6ODZ2N{Ow
I 9.2	NILP[ZNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M4jEb\|ExKM7:TR?=	M3zwOWROW09?	NWD2dWpITUN3ME24NEBvVQ>?	NXvpdXoyOTlyNkS3N\|A>
LOUCY	M4naS2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NFHnRWoyOCEQvF2=	NHzH[oRFVVOR	M17aXGVEPTB;MUG3JI5O	NIDxb\|AyQTB4NEezNC=>
J.RT3-T3.5	NIO3SnNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M1juRVExKM7:TR?=	MXfEUXNQ	M3X2OGVEPTB;MUKzJI5O	MoP4NVkxPjR5M{C=
800000	MYHHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M4S0cFExKM7:TR?=	NVH4R5pkTE2VTx?=	MmHOSWM2OD1zNkOgcm0>	NIPPeJMyQTB4NEezNC=>
Jurkat	NHvZe49Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M3H1U\|ExKM7:TR?=	M4rldmROW09?	M{W1SGVEPTB;MkK1JI5O	M4fGXlE6ODZ2N{Ow
MOLT-4	MUnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M3;yOVExKM7:TR?=	NFXQcWhFVVOR	M33mUmVEPTB;MkOyJI5O	NFjQdlEyQTB4NEezNC=>
Molt-16	NX;lVoJJT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NWjZbYZxOTBizszN	MUDEUXNQ	NELFcW1GSzVyPUK0NUBvVQ>?	NUGyPIRmOTlyNkS3N\|A>
CEM/C3	NV3KTXhjT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MoPjNVAh\|ryP	MlfNSG1UVw>?	M3\q[GVEPTB;MkW3JI5O	MoC1NVkxPjR5M{C=
CEM/C2	M3XTbmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	M1HDclExKM7:TR?=	NWLJWIpCTE2VTx?=	M3\ofmVEPTB;MkexJI5O	M4LMVVE6ODZ2N{Ow
CCRFCEM	NV3o[plxT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NUnkb5FKOTBizszN	NVTrfYg5TE2VTx?=	M{nMZmVEPTB;M{K3JI5O	NYm0UIUzOTlyNkS3N\|A>
CEM/C1	M{X1eGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	M1Lvc\|ExKM7:TR?=	NEjvWFZFVVOR	MofOSWM2OD1\|OEKgcm0>	M2O3XFE6ODZ2N{Ow
SUPTI[VB]	NX;jNG1[T3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MoX2NVAh\|ryP	Ml\KSG1UVw>?	MlvZSWM2OD14MUmgcm0>	NEPzVpcyQTB4NEezNC=>
CCRF–HSB-2	NXLVSmtMT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NXjCVJVPOTBizszN	MV;EUXNQ	MnL3SWM2OD1{MUG3JI5O	NVrSelQ4OTlyNkS3N\|A>
I 2.1	MVfBdI9xfG:\|aYOgZZN{[Xl?	Mn\tNVAh\|ryP	NHL6NFdFVVOR	MV3pcoR2[2W\|IHHwc5B1d3Orcx?=	MnjNNVkxPjR5M{C=
I 9.2	M4XaOGFxd3C2b4Ppd{Bie3OjeR?=	M3zyZ\|ExKM7:TR?=	MnLZSG1UVw>?	MVfpcoR2[2W\|IHHwc5B1d3Orcx?=	M2q0[FE6ODZ2N{Ow
A3	MniyRZBweHSxc3nzJIF{e2G7	Mk\BNVAh\|ryP	NVS4UmZlTE2VTx?=	Ml7BbY5lfWOnczDhdI9xfG:\|aYO=	M{HuV\|E6ODZ2N{Ow
RD	NHHsWYZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NYjxS2hpOTBizszN		M3HWb2lEPTB-MUCg{txO	NEfsZZAzODd2ME[yNy=>
Rh41	MXHHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	M{K2PVExKM7:TR?=		NHS4UItKSzVyPUOzMlghdk1?	MUKyNFc1ODZ{Mx?=
Rh18	NXyzVZJsT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NUDPbHFtOTBizszN		NEjSVY1KSzVyPUOwN{BvVQ>?	NEjyPFEzODd2ME[yNy=>
Rh30	MljoS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	NIDrUXMyOCEQvF2=		MXHJR\|UxRTRwOEGg{txO	M2nrOVIxPzRyNkKz
BT-12	M{HTOWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	M1GzdFExKM7:TR?=		NXXUbYl4UUN3ME6xNEDPxE1?	NUHt[VB{OjB5NEC2NlM>
CHLA-266	M4jsfWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NE\NfpAyOCEQvF2=		MV3JR\|UxRTFwMkKg{txO	NWTOU4VZOjB5NEC2NlM>
TC-71	M1Lodmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NIrSVZkyOCEQvF2=		MmTYTWM2OD1{LkWyJO69VQ>?	NXPsXVJJOjB5NEC2NlM>
CHLA-9	NIPCSpdIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NWXEO4JOOTBizszN		NGDXcYRKSzVyPUW5NUBvVQ>?	NELQS2EzODd2ME[yNy=>
CHLA-10	MYjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	MXmxNEDPxE1?		NIDIWFdKSzVyPUGwNkBvVQ>?	MUiyNFc1ODZ{Mx?=
CHLA-258	NX;IXHhuT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MUexNEDPxE1?		NFrOXJhKSzVyPUGuNFUh\|ryP	NI[3bI8zODd2ME[yNy=>
GBM2	M1zoNWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MonYNVAh\|ryP		M1q5V2lEPTB;OT6xOUDPxE1?	MWOyNFc1ODZ{Mx?=
NB-1643	M4LNXGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NYPxT2c4OTBizszN		NYDVWllOUUN3ME21MlQh\|ryP	NUmwfox2OjB5NEC2NlM>
NB-Ebc1	NXrEfI5OT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NYX1TpVkOTBizszN		NFfNc25KSzVyPkGwJO69VQ>?	NFnkVZEzODd2ME[yNy=>
CHLA-90	M{D4Nmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	NFrSb5EyOCEQvF2=		NYnNcFB7UUN3ME6xNEDPxE1?	NWWzO\|NQOjB5NEC2NlM>
CHLA-136	NYr3[YNmT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	NFu2RngyOCEQvF2=		NUjWXWNXUUN3ME6xNEDPxE1?	NIDsUFgzODd2ME[yNy=>
NALM-6	NHn6VYZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M4qyZ\|ExKM7:TR?=		M{X6UGlEPTB;Mk[1JI5O	NGXBW3kzODd2ME[yNy=>
COG-LL-317	M1nXfWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MlLLNVAh\|ryP		MVnJR\|UxRTZwNEmgcm0>	MUOyNFc1ODZ{Mx?=
RS4;11	M{nxSmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7	MonkNVAh\|ryP		MkXlTWM2OD1zNEegcm0>	MoTkNlA4PDB4MkO=
MOLT-4	NFLLTnhIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	NH3M[owyOCEQvF2=		MmrKTWM2OD12MDDuUS=>	NHPjSW0zODd2ME[yNy=>
CCRF-CEM	NWPybFNjT3Kxd4ToJIlvcGmkaYTvdpkh[XO\|YYm=	MVKxNEDPxE1?		NFnBd5VKSzVyPUK2PEBvVQ>?	MoLXNlA4PDB4MkO=
Kasumi-1	MUnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?	MmTFNVAh\|ryP		MVPJR\|UxRTFyNzDuUS=>	MVqyNFc1ODZ{Mx?=
Karpas-299	MnzPS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?	M4[xUlExKM7:TR?=		M37VTWlEPTB;Mj65N{DPxE1?	MXmyNFc1ODZ{Mx?=
Ramos-RA1	NFqzcoxIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=	M2TyeVExKM7:TR?=		MUXJR\|UxRTdwM{Wg{txO	NEn2[oIzODd2ME[yNy=>
H1299	NYS3SVAzU2mwYYPlJIF{e2G7	MXqxNEDPxE1?		MULpcohq[mm2czDJT2JMTS2rbnT1Z4VlKEGtdDDBZ5RqfmG2aX;u	NXLpZ4lIOjF7MEi2NVY>

Click to View More Cell Line Experimental Data

Assay

Methods	Test Index	PMID

Western blot	cMET / p-cMET / p-AKT / p-ERK / p-rpS6	23022995
Growth inhibition assay	Cell viability	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 (from reference)

Kinase Assay:^[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.
Cell Research:^[1]	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]	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)

References

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	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	C1CC2=C3C(=CC=C2)C(=CN3C1)C4C(C(=O)NC4=O)C5=CNC6=CC=CC=C65

Download Tivantinib (ARQ 197) SDF

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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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

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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

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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.

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