Crizotinib (PF-02341066) 化学構造
分子量: 450.34

高品質保証

文献中の引用(65)

カスタマーフィードバック(8)

Quality Control & MSDS

製品説明

  • Compare c-Met Inhibitors
    c-Met製品生物活性の比較
  • 研究分野
  • Combination Therapy
    併用療法
  • Crizotinib (PF-02341066)のメカニズム

製品の説明

生物活性

製品説明 Crizotinib (PF-02341066) は1種の有効な小分子の卵白の阻害剤の再編人プロテインキナーゼ、 Kiが 4 nM。
ターゲット c-Met ALK
IC50 11 nM 24 nM [1]
In vitro試験 PF-2341066 displays similar potency against c-Met phosphorylation in mIMCD3 mouse or MDCK canine epithelial cells with IC50 of 5 nM and 20 nM, respectivly. PF-2341066 shows improved or similar activity against NIH3T3 cells engineered to express c-Met ATP-binding site mutants V1092I or H1094R or the P-loop mutant M1250T with IC50 of 19 nM, 2 nM and 15 nM, respectively, compared with NIH3T3 cells expressing wild-type receptor with IC50 of 13 nM. In contrast, a marked shift in potency of PF-2341066 is observed against cells engineered to express c-Met activation loop mutants Y1230C and Y1235D with IC50 of 127 nM and 92 nM, respectively, compared with wild-type receptor. PF-2341066 also potently prevents the phosphorylation of c-Met in NCI-H69 and HOP92 cells, with IC50 of 13 nM and 16 nM, respectively, which express the endogenous c-Met variants R988C and T1010I, respectively. PF-2341066 is >1,000-fold selective for the VEGFR2 and PDGFRβ RTKs, >250-fold selective for IRK and Lck, and ∼40- to 60-fold selective for Tie2, TrkA, and TrkB, all compared with c-Met. PF-2341066 is 20- to 30-fold selective for RON and Axl RTKs. In contrast, PF-2341066 shows a near-equivalent IC50 of 24 nM against the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) oncogenic fusion variant of the ALK RTK expressed by the KARPAS299 human anaplastic large cell lymphoma (ALCL) cell line. PF-2341066 inhibits c-Met–dependent neoplastic phenotypes of cancer cells and angiogenic phenotypes of endothelial cells. PF-2341066 suppresses human GTL-16 gastric carcinoma cell growth with IC50 of 9.7 nM. PF-2341066 induces apoptosis in GTL-16 cells with IC50 of 8.4 nM. PF-2341066 inhibits HGF-stimulated human NCI-H441 lung carcinoma cell migration and invasion with IC50 of 11 nM and 6.1 nM, respectively. PF-2341066 inhibits MDCK cell scattering with IC50 of 16 nM. PF-2341066 prevents HGF-stimulated c-Met phosphorylation, cell survival, and Matrigel invasion with IC50 of 11 nM, 14 nM and 35 nM, respectively. In addition, PF-2341066 prevents serum-stimulated HMVEC branching tubulogenesis (formation of vascular tubes) in fibrin gels. [1] PF-2341066 also potently inhibits NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells with an IC50 of 24 nM. PF-2341066 potently prevents cell proliferation, which is associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells with IC50 of 30 nM, but not ALK-negative lymphoma cells. [2] Besides, PF-2341066 prevents osteosarcoma behavior associated with primary tumor growth (i.e., proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
BAF3 NY\3eG8{S3m2b4TvfIlkKEG|c3H5 NE\aUFI1QCCq NYXoTok6TE2VTx?= M4fOT2N6fG:2b4jpZ4l1gSCjZ3HpcpN1KG2xdYPlJGJCTjNiY3XscJMh\XiycnXzd4lv\yCDTFugSlEyPzSOIH31eIFvfCClb3X4dJJme3OrbnegSW1NPCC5aYToJGlEPTBib3[gNE43OiEQvF2= MlnRNlE2PzJ3OEm=
BAF3 M3O3[mN6fG:2b4jpZ{BCe3OjeR?= NVm1XpRUPDhiaB?= M2HrZ2ROW09? MXfDfZRwfG:6aXPpeJkh[WejaX7zeEBud3W|ZTDCRWY{KGOnbHzzJIV5eHKnc4PpcochSUyNIFyxNVk3VSCvdYThcpQh[2:neIDy[ZN{cW6pIFXNUFQhf2m2aDDJR|UxKG:oIEKuNkDPxE1? NXHx[4Y5OjF3N{K1PFk>
BAF3 MWrDfZRwfG:6aXOgRZN{[Xl? NVXkSIluPDhiaB?= NVT6dnJoTE2VTx?= MX7DfZRwfG:6aXPpeJkh[WejaX7zeEBud3W|ZTDCRWY{KGOnbHzzJIV5eHKnc4PpcochTU2OND3BUGshf2m2aDDJR|UxKG:oIECuNlgh|ryP NFWwPY4zOTV5MkW4PS=>
Kelly NWrQR2l7S3m2b4TvfIlkKEG|c3H5 MVnEUXNQ NF;KUGREgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBM\WyueTDj[YxteyCneIDy[ZN{cW6pIFHMT{BHOTF5NFygcZV1[W62IIfpeIghUUN3MDDv[kAxNjR{IN88US=> NVTmPI1xOjF3N{K1PFk>
SH-SY5Y NXLiXo9GS3m2b4TvfIlkKEG|c3H5 M{LRXGROW09? MnLER5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gV2guW1l3WTDj[YxteyCneIDy[ZN{cW6pIFHMT{BHOTF5NFygcZV1[W62IIfpeIghUUN3MDDv[kAxNjV|IN88US=> NF3V[HozOTV5MkW4PS=>
SMS-KCN MWTDfZRwfG:6aXOgRZN{[Xl? MkLzSG1UVw>? MkjOR5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gV21UNUuFTjDj[YxteyCneIDy[ZN{cW6pIFHMT{BTOTJ5NWGgcZV1[W62IIfpeIghUUN3MDDv[kAxNjlzIN88US=> NGPYeIszOTV5MkW4PS=>
BAF3 MWPDfZRwfG:6aXOgRZN{[Xl? M2LBfVQ5KGh? NEn6PZBFVVOR NWX6cGtQS3m2b4TvfIlkcXS7IHHnZYlve3RibX;1d4UhSkGIMzDj[YxteyCneIDy[ZN{cW6pIGTlcE1CVEtid3n0bEBKSzVyIH;mJFAvOTlizszN NF;u[nAzOTV5MkW4PS=>
3T3 M{npSWZ2dmO2aX;uJGF{e2G7 M1qyV|EhcA>? NEfHc|FFVVOR MVvJcohq[mm2aX;uJI9nKFKRTjDhd5Nme3OnZDDhd{Boem:5dHig[oFkfG:{LXnu[JVk\WRiYYX0c5Bpd3OyaH;yfYxifGmxbjD3bZRpKEmFNUCgc4YhOC5yODFOwG0> NYfUT4F{OjF6MUK0NVQ>
3T3-E MWnGeY5kfGmxbjDBd5NigQ>? NXP2XWFDOSCq MWrEUXNQ MkK0TY5pcWKrdHnvckBw\iCWSVWyJIF{e2W|c3XkJIdzd3e2aDDmZYN1d3JvaX7keYNm\CCjdYTvdIhwe3Cqb4L5cIF1cW:wIIfpeIghUUN3MDDv[kAxNjR2ODFOwG0> Ml\nNlE5OTJ2MUS=
A549 NEjjXFFMcW6jc3WgRZN{[Xl? NHvIeJYyKGh? M{jPV2ROW09? MYjJcohq[mm2aX;uJI9nKGi3bXHuJJJm[2:vYnnuZY51KGNvTVXUJItqdmG|ZTDlfJBz\XO|ZXSgZZN{\XO|ZXSgZZMhcW6qaXLpeIlwdiCxZjDIS2YucW6mdXPl[EBifXSxcHjvd5Bpd3K7bHH0bY9vKHerdHigTWM2OCCxZjCwMlAxQCEQvF2= MmLSNlE5OTJ2MUS=
BAF3-BCL MWfGeY5kfGmxbjDBd5NigQ>? NVLCU5JLOSCq M4q5emROW09? MkTzTY5pcWKrdHnvckBw\iCDQlygZZN{\XO|ZXSgZZMh\3Kxd4ToJIZi[3Sxcj3pcoR2[2WmIHH1eI9xcG:|cHjvdplt[XSrb36ge4l1cCCLQ{WwJI9nKDFwMUW5JO69VQ>? NGjtN4MzOThzMkSxOC=>
HEK293 MWTGeY5kfGmxbjDBd5NigQ>? NVrUZZNzOSCq MXTEUXNQ M3f5S2lvcGmkaYTpc44hd2ZiQWjMJIF{e2W|c3XkJIF{KGe{b4f0bEBn[WO2b4KtbY5lfWOnZDDheZRweGixc4Doc5J6dGG2aX;uJJdqfGhiSVO1NEBw\iByLkK5OEDPxE1? MVqyNVgyOjRzNB?=
HEK293 MmfWSpVv[3Srb36gRZN{[Xl? Mn7GNUBp M4rrdGROW09? MoLqTY5pcWKrdHnvckBw\iCLUjDhd5Nme3OnZDDhd{Boem:5dHig[oFkfG:{LXnu[JVk\WRiYYX0c5Bpd3OyaH;yfYxifGmxbjD3bZRpKEmFNUCgc4YhOi56OEeg{txO NH7BfVAzOThzMkSxOC=>
Jurkat MXLGeY5kfGmxbjDBd5NigQ>? MVuxJIg> M3rCOWROW09? NEf4U3hKdmirYnn0bY9vKG:oIFzDT{Bie3Onc4Pl[EBieyCpcn;3eIgh\mGldH;yMYlv\HWlZXSgZZV1d3Cqb4PwbI9zgWyjdHnvckB4cXSqIFnDOVAhd2ZiMj63OFEh|ryP NV\FS2w1OjF6MUK0NVQ>
KARPAS299 MYHLbY5ie2ViQYPzZZk> MXuxJIg> MnnySG1UVw>? NVruN5V{UW6qaXLpeIlwdiCxZjDBUGsh[XO|ZYPz[YQh[XNiZ4Lve5RpKG[jY4Tvdk1qdmS3Y3XkJIF2fG:yaH;zdIhwenmuYYTpc44hf2m2aDDJR|UxKG:oIECuNFIh|ryP M{fi[VIyQDF{NEG0
PAE M3voUmZ2dmO2aX;uJGF{e2G7 M2rlOlEhcA>? NUfTSG9QTE2VTx?= NETNeotKdmirYnn0bY9vKG:oIGTST2Ih[XO|ZYPz[YQh[XNiZ4Lve5RpKG[jY4Tvdk1qdmS3Y3XkJIF2fG:yaH;zdIhwenmuYYTpc44hf2m2aDDJR|UxKG:oIECuN|k6KM7:TR?= MnrrNlE5OTJ2MUS=
BAF3 NXzRR|lrTnWwY4Tpc44hSXO|YYm= M1TmVFIuOyCm MlXRSG1UVw>? MnrETY5pcWKrdHnvckBw\iCWRVyt[pV{\WRiaX7zeYxqdiC{ZXPldJRweiCneIDy[ZN{\WRid3n0bEBKSzVyIH;mJFEvPjR|IN88US=> Mn;SNlM4PDJ{NUK=
KARPAS299 NF;pbWlEgXSxdH;4bYMhSXO|YYm= M{j2W|IuOyCm M3m5T2ROW09? M1nwTmlEPTB;MD6wOlQzKM7:TR?= MnzQNlM4PDJ{NUK=
EBC1 MlfXS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{K1W|czKGh? NEXZXZBFVVOR MnTkTWM2OD1yLkCyN{DPxE1? MVOyN|k6OzN{OB?=
HCT116 NIXWXXVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWDwelRjPzJiaB?= MYjEUXNQ MnzQTWM2OD1zND64NkDPxE1? MVyyN|k6OzN{OB?=
MCF7 MorXS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3H2T|czKGh? Ml:5SG1UVw>? M3v0cGlEPTB;OT61PEDPxE1? M{HDNVI{QTl|M{K4
MDA-MB-231 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlfXO|IhcA>? MYTEUXNQ MkDITWM2OD1zMD64JO69VQ>? M3vKWFI{QTl|M{K4
MKN45 MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mm\QO|IhcA>? MnHRSG1UVw>? M2rNcWlEPTB;MD6wNVMh|ryP NH2zZmkzOzl7M{OyPC=>
NCI-H441 NWrqWFhKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWm3NkBp NVLtNW06TE2VTx?= M1GxPWlEPTB;MUeuNlUh|ryP MXSyN|k6OzN{OB?=
NCI-H661 NH70OI1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXTi[lFbPzJiaB?= NEDY[3RFVVOR MnP4TWM2OD1zMT60O{DPxE1? MnTQNlM6QTN|Mki=
SK-MEL-28 MkT2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnLNO|IhcA>? NUHIdHFITE2VTx?= NYDrZWR4UUN3ME2xNE46PyEQvF2= NYTVbWVwOjN7OUOzNlg>
SKOV3 NE\N[4RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MojiO|IhcA>? M1jvVWROW09? NGPlXJRKSzVyPUGyMlg2KM7:TR?= NIL5Z2QzOzl7M{OyPC=>
SNU5 NEDtfmlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnS0O|IhcA>? M33sWGROW09? MoC4TWM2OD1yLkCxOkDPxE1? NIrYZYwzOzl7M{OyPC=>
NCI-H2228 NEfhc|JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHyyV244OiCq NYrEbYdqTE2VTx?= MWDJcohq[mm2aX;uJI9nKEGOSz3meZNqd25iZILpeoVvKGOnbHygdJJwdGmoZYLheIlwdiC5aYToJGlEPTBib3[gNE4yOThizszN NYnLeowzOjR2M{K5NFk>
NCI-H3122 MlW5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3vJ[VczKGh? MmLESG1UVw>? MW\Jcohq[mm2aX;uJI9nKEGOSz3meZNqd25iZILpeoVvKGOnbHygdJJwdGmoZYLheIlwdiC5aYToJGlEPTBib3[gNE4yODhizszN NIP1e4wzPDR|MkmwPS=>
NCI-H3122 MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnvPO|IhcA>? MlHMSG1UVw>? M1XETWlvcGmkaYTpc44hd2ZiQVzLMYZ2e2mxbjDkdol3\W5iY3XscEBxem:uaX\ldoF1cW:wIHnuJIh2dWGwIF7DTU1JOzF{MjDj[YxteyCqYYLic5JqdmdiQVzLJGcyOjZ7QTDteZRidnRid3n0bEBKSzVyIH;mJFAvPjJ|IN88US=> Mnf5NlQ1OzJ7MEm=
NCI-H3122 NGXmRmpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnzRO|IhcA>? NGj4d4lFVVOR MXLJcohq[mm2aX;uJI9nKEGOSz3meZNqd25iZILpeoVvKGOnbHygdJJwdGmoZYLheIlwdiCrbjDoeY1idiCQQ1mtTFMyOjJiY3XscJMhcGG{Yn;ybY5oKEGOSzDMNVE6Pk1ibYX0ZY51KHerdHigTWM2OCCxZjCwMlg{QCEQvF2= NHXIPGczPDR|MkmwPS=>
NIH-3T3 MlHUT4lv[XOnIFHzd4F6 MnrPNUBp MlTBSG1UVw>? NEjTbmFKdmirYnn0bY9vKG:oIHj1cYFvKHerbHSgeJlx\SCHTVy0MYZ2e2WmIFHMT{BmgHC{ZYPz[YQh[XO|ZYPz[YQh[XNicHjvd5Bpd3K7bHH0[YQhSUyNIHzleoVtKHerdHigTWM2OCCxZjCwMlA5KM7:TR?= MXyyOFQ{OjlyOR?=
NIH-3T3 MnfyT4lv[XOnIFHzd4F6 MUixJIg> M3uxVGROW09? NUjEV4ZKUW6qaXLpeIlwdiCxZjDoeY1idiCHTVy0MYZ2e2WmIFHMT{BIOTJ4OVGgcZV1[W62IHX4dJJme3OnZDDhd5Nme3OnZDDhd{BxcG:|cHjvMWFNUyCuZY\lcEB4cXSqIFnDOVAhd2ZiMD62NFUh|ryP MlLoNlQ1OzJ7MEm=
NIH-3T3 NV;2T|VYU2mwYYPlJGF{e2G7 MYexJIg> NYjnU2lITE2VTx?= MnLtTY5pcWKrdHnvckBw\iCqdX3hckBGVUx2LX\1d4VlKEGOSzDTNVIxPllibYX0ZY51KGW6cILld5Nm\CCjc4Pld5Nm\CCjczDwbI9{eGixLVHMT{Bt\X[nbDD3bZRpKEmFNUCgc4YhOC54Mk[g{txO MWmyOFQ{OjlyOR?=
NIH-3T3 NHnuZ2xMcW6jc3WgRZN{[Xl? NVvUeHV3OSCq NIfodJlFVVOR MlXlTY5pcWKrdHnvckBw\iCqdX3hckBGVUx2LX\1d4VlKEGOSzDMNVE6Pk1ibYX0ZY51KGW6cILld5Nm\CCjc4Pld5Nm\CCjczDwbI9{eGixLVHMT{Bt\X[nbDD3bZRpKEmFNUCgc4YhOC56NEOg{txO M1Xuc|I1PDN{OUC5
NIH-3T3 MXjLbY5ie2ViQYPzZZk> Mni2NUBp M1PQfmROW09? NVywOVJTUW6qaXLpeIlwdiCxZjDoeY1idiCHTVy0MYZ2e2WmIFHMT{BNOTF3MmKgcZV1[W62IHX4dJJme3OnZDDhd5Nme3OnZDDhd{BxcG:|cHjvMWFNUyCuZY\lcEB4cXSqIFnDOVAhd2ZiMT6wNlYh|ryP MYWyOFQ{OjlyOR?=
BAF3 NWDHT3RTTnWwY4Tpc44hSXO|YYm= NH3PXHA4OiCq Mk\oSG1UVw>? NILJR45KdmirYnn0bY9vKG:oIF7QUU9CVEtidILhcpNn\WO2ZXSgZZN{\XO|ZXSgZZMh[2WubDDndo94fGhiaX7obYJqfGmxbjD3bZRpKEmFNUCgc4YhOC5yNUGg{txO NH;xXG8zPDR4OE[zNi=>
BAF3 NGXjeHBEgXSxdH;4bYMhSXO|YYm= NG\0VW44OiCq NVLTOHcyTE2VTx?= NEftU4hKSzVyPUCuPVgh|ryP NGX3e3IzPDR4OE[zNi=>
NIH-3T3 MXfLbY5ie2ViQYPzZZk> MU[xJIg> NXq5NWdZUW6qaXLpeIlwdiCxZjDoeY1idiCHTVy0MYZ2e2WmIFHMT{BHOTF5NFygcZV1[W62IHX4dJJme3OnZDDhd5Nme3OnZDDhd{BxcG:|cHjvMWFNUyCuZY\lcEB4cXSqIFnDOVAhd2ZiMD6xOlUh|ryP NV3BeXhUOjR6MUmxNVY>
NIH-3T3 M1vQ[WtqdmG|ZTDBd5NigQ>? M2XXU|EhcA>? Moi2TY5pcWKrdHnvckBw\iCqdX3hckBGVUx2LX\1d4VlKEGOSzDDNVE2PllibYX0ZY51KGW6cILld5Nm\CCjc4Pld5Nm\CCjczDwbI9{eGixLVHMT{Bt\X[nbDD3bZRpKEmFNUCgc4YhOC52N{ig{txO M3G0bFI1QDF7MUG2
NIH-3T3 M3PoUGtqdmG|ZTDBd5NigQ>? MX:xJIg> MUXJcohq[mm2aX;uJI9nKGi3bXHuJGVOVDRvZoXz[YQhSUyNIFexNlAzWiCvdYThcpQh\XiycnXzd4VlKGG|c3Xzd4VlKGG|IIDoc5NxcG9vQVzLJIxmfmWuIIfpeIghUUN3MDDv[kAyNjF2ODFOwG0> NXHRXmN[OjR6MUmxNVY>
NIH-3T3 MUnLbY5ie2ViQYPzZZk> M4L2PVEhcA>? MWDJcohq[mm2aX;uJI9nKGi3bXHuJGVOVDRvZoXz[YQhSUyNIEGxOVFVcW6|IH31eIFvfCCneIDy[ZN{\WRiYYPz[ZN{\WRiYYOgdIhwe3Cqbz3BUGshdGW4ZXyge4l1cCCLQ{WwJI9nKDNwMEO5JO69VQ>? MoDpNlQ5OTlzMU[=
KARPAS299 MWjLbY5ie2ViQYPzZZk> MoDmPVAhdWmw M4nRZ2ROW09? MnnWTY5pcWKrdHnvckBw\iCQUF2t[pV{\WRiQVzLJJBpd3OyaH;yfYxifGmxbjDlfJBz\XO|ZXSge4l1cCCLQ{WwJI9nKDBwMUGg{txO MYqyOFkxODd3MB?=
MKN 45 M1POd2tqdmG|ZTDBd5NigQ>? MlezNUBp NI[yWm5FVVOR MkjvTY5pcWKrdHnvckBw\iClLV3leEBxcG:|cHjvdplt[XSrb36ge4l1cCCLQ{WwJI9nKDBwMEKg{txO NY\LT5pZOjR7MEC3OVA>
A549 MnHVR5l1d3SxeHnjJGF{e2G7 NUKzOHk6PDhiaB?= MlfRSG1UVw>? NXrpOnk2UUN3MDDv[kA1NjB6NDFOwG0> MU[yOFkxODh|MB?=
NCI-H1975 NUHXenpRS3m2b4TvfIlkKEG|c3H5 MYm0PEBp M2T5T2ROW09? Mn7BTWM2OCCxZjC3MlU2OSEQvF2= MlPINlQ6ODB6M{C=
NCI-H1993 MXHDfZRwfG:6aXOgRZN{[Xl? NVTx[oRKPDhiaB?= NEezXm5FVVOR MWPJR|UxKG:oIECuNFYyKM7:TR?= NEnlXlQzPDlyMEizNC=>
NCI-H1993 NES2NJBCeG:2b4Ppd{BCe3OjeR?= M3z4TFEh|ryP MY[yOEBp NV;iTIxtTE2VTx?= M1K5fYRw\XNibn;0JIlv\HWlZTDhdI9xfG:|aYO= NFrPeIgzPDlyMEizNC=>
NIH-3T3 MXnDfZRwfG:6aXOgRZN{[Xl? NXX6dVloPDhiaB?= M4DZd2ROW09? NVK5eHFZUUN3MDDv[kAxNjN4NDFOwG0> M2jMOVI1QTByOEOw
EBC1 MnviS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIXwVVU4OiCq NWnIb2VyTE2VTx?= M1jW[GlEPTBib3[gNE4xODZ7IN88US=> NIi4U|EzPDlyMEizNS=>
KARPAS299 M2TkRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlrLO|IhcA>? MXzEUXNQ M{D4fWlEPTBib3[gNE4zKM7:TR?= NYezSYF2OjR7MEC4N|E>
NB1 MkTBS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWe5[olLUUN3ME25NU46QCCwTR?= NVfXPVNpW0GQR1XS
NCI-SNU-5 NHexUW1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1fTcGlEPTB;MUC1Mlc2KG6P M2q2S3NCVkeHUh?=
SR MkTjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NILGd4VKSzVyPUGyOk4{OSCwTR?= NG[zb|dUSU6JRWK=
SF539 M4LMSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEftTlZKSzVyPUKwOE4zPCCwTR?= MV7TRW5ITVJ?
SU-DHL-1 M4\Ifmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIL4cndKSzVyPUOzOk45OiCwTR?= NWntSlBuW0GQR1XS
SCC-3 NV2zNFhxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{LKXmlEPTB;M{W2Mlc3KG6P MXrTRW5ITVJ?
DEL NEnDT4FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHLWb5dKSzVyPUO2PU46KG6P NWnXfllmW0GQR1XS
CTV-1 M37yW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFjaPY9KSzVyPUW5Ok41QCCwTR?= NFq0OItUSU6JRWK=
EM-2 MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUe5e3JXUUN3ME22NFEvOzRibl2= MoTVV2FPT0WU
MHH-CALL-2 MnjhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVjJR|UxRTZ6Mj61O{BvVQ>? M{DCSnNCVkeHUh?=
KM12 MonWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2q3cGlEPTB;N{C2Mlkhdk1? MUHTRW5ITVJ?
KINGS-1 NIr6eolIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MWHJR|UxRTd2OT63OUBvVQ>? MY\TRW5ITVJ?
MEG-01 NHHXNpNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVnJR|UxRTh3Nz62OkBvVQ>? NHXxeFVUSU6JRWK=
BV-173 Mn60S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGrudGJKSzVyPUGuNFU6QTdizszN M17vNXNCVkeHUh?=
LAMA-84 NIPmS5BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHu2PWJKSzVyPUGuN|gzQDJizszN MoKzV2FPT0WU
KARPAS-299 NU\kUIhFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUj1OnBGUUN3ME2xMlQxQDZzIN88US=> NYPje|dIW0GQR1XS
K-562 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWW4OZFOUUN3ME2xMlczOjZ7IN88US=> MnnzV2FPT0WU
SK-LMS-1 NFe0R5pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Ml\6TWM2OD1zLke2PFY4KM7:TR?= NHj1NVJUSU6JRWK=
MOLT-16 M4\zTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHfScWZKSzVyPUGuPVU2PzVizszN MlqzV2FPT0WU
CMK MmXYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWLJR|UxRTFwOU[xOVkh|ryP NXXRNHdlW0GQR1XS
ST486 NWXxVJRyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVLJR|UxRTJwNEOwO|Mh|ryP NUPEd|dMW0GQR1XS
CI-1 MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MU\JR|UxRTJwNEm2OVkh|ryP NV;ITI8yW0GQR1XS
KP-N-RT-BM-1 M4fvbWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWHJR|UxRTJwN{CxNlIh|ryP NEH6XVZUSU6JRWK=
ALL-PO NYfSUmYxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUWyNVh5UUN3ME2zMlE5OjB5IN88US=> NYXnTGlvW0GQR1XS
KS-1 M1:4Vmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnfKTWM2OD1|LkKxNlI2KM7:TR?= NI\Mc3NUSU6JRWK=
Becker NVvQSFVoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MljhTWM2OD12LkKzPVMh|ryP NVm0OZVDW0GQR1XS
GDM-1 MkfjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWXSS4JsUUN3ME20MlI1PjF5IN88US=> NE\2WXNUSU6JRWK=
BC-1 MnvYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoD1TWM2OD12LkS5Nlc4KM7:TR?= NVXZfGhNW0GQR1XS
NB14 NYHwW5J{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NETZTIdKSzVyPUSuPFM2OjRizszN NXTKc2lMW0GQR1XS
NOS-1 NGXpRW1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlLGTWM2OD13LkOzPFc1KM7:TR?= MYnTRW5ITVJ?
MZ1-PC NXHl[nd{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NV;4c5BRUUN3ME21MlgzOTVzIN88US=> MVrTRW5ITVJ?
A498 MnruS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MljOTWM2OD14LkC4OFc{KM7:TR?= MoO3V2FPT0WU
EW-16 NXLyfG12T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXjvRnczUUN3ME22MlM4Pzd|IN88US=> NGnMNY1USU6JRWK=
NALM-6 Ml[3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoTCTWM2OD14Lk[4N|g4KM7:TR?= MoXwV2FPT0WU
EB-3 M3LKcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWi2NZpNUUN3ME23MlA4OjN|IN88US=> NX7RW5ZvW0GQR1XS
697 MoLuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnLXTWM2OD17LkK0N|I6KM7:TR?= NVPqSXhzW0GQR1XS
Ramos-2G6-4C10 MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MljITWM2OD17LkW5PFQzKM7:TR?= Mo\zV2FPT0WU
KNS-81-FD NYT4NYJ3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkiyTWM2OD17Lk[5OlU{KM7:TR?= NYfwOHRGW0GQR1XS
HUTU-80 MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2T6UGlEPTB;OT63OFY1OiEQvF2= NXj5UHgzW0GQR1XS
LS-411N MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml\ITWM2OD1zMD6wOVY4KM7:TR?= MmL5V2FPT0WU
RPMI-8402 Mn\0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWTJR|UxRTFyLkGxOkDPxE1? M13kcXNCVkeHUh?=
KU812 MojPS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUTFWpUyUUN3ME2xNE4zQTlzIN88US=> NIjpcnVUSU6JRWK=
EW-1 M3vRWGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmPVTWM2OD1zMD60OFI2KM7:TR?= NH3tbpRUSU6JRWK=
HC-1 M1qyTGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVfJR|UxRTFyLkS4OFQh|ryP MlLkV2FPT0WU
NB69 M1;0S2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYTJR|UxRTFyLkWwOFMh|ryP M4\sXnNCVkeHUh?=
MFH-ino MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkLiTWM2OD1zMD64N|A{KM7:TR?= MUfTRW5ITVJ?
CCRF-CEM NHXxWmRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYXJR|UxRTFzLkW5O{DPxE1? MkPsV2FPT0WU
SK-N-DZ NXvwfIVvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVvJR|UxRTF{LkC0N|Yh|ryP NVThZnFiW0GQR1XS
NCI-H720 MlXES5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWDJR|UxRTF{LkG3NFUh|ryP NH7HRWFUSU6JRWK=
HCC1187 MoTqS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV7OXWs6UUN3ME2xNk4zODRzIN88US=> NFHiW41USU6JRWK=
IST-SL2 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlrYTWM2OD1zMj60PFczKM7:TR?= NHf5SpNUSU6JRWK=
KE-37 NGP6VllIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGPEdodKSzVyPUGyMlc6PjZizszN MX3TRW5ITVJ?
HCC1599 M4j1S2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4HmVmlEPTB;MUKuPVA3QSEQvF2= NXjwVHU{W0GQR1XS
A4-Fuk M171NWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NETDTJdKSzVyPUGyMlk2QDZizszN M2X1fHNCVkeHUh?=
NKM-1 NGHBUo9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3jSUGlEPTB;MUOuNlkzPSEQvF2= NI\G[oVUSU6JRWK=
BE-13 MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnezTWM2OD1zMz63PVg6KM7:TR?= NWO2TZRSW0GQR1XS
MV-4-11 Ml\DS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWTWb3drUUN3ME2xOE4xOzJ2IN88US=> NHXTe4dUSU6JRWK=
OPM-2 M3jwO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHfURnJKSzVyPUG0MlQxQDVizszN NEHrRYxUSU6JRWK=
KARPAS-422 NUexZohGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWnJR|UxRTF2LkWxNlYh|ryP MoHMV2FPT0WU
RPMI-8226 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4jMNGlEPTB;MUSuPFkyPSEQvF2= NEiyTYxUSU6JRWK=
KARPAS-45 M1rwZ2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXPJR|UxRTF3Lke3NVYh|ryP Mnz1V2FPT0WU
SK-PN-DW NYD2O|B[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFPXPYdKSzVyPUG1Mlg3OzFizszN MlrzV2FPT0WU
LC-2 NWPUdIJ3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{DtdGlEPTB;MU[uNVUxPiEQvF2= MkHMV2FPT0WU
NCI-H1648 MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV60O41CUUN3ME2xOk4zPTRizszN MXzTRW5ITVJ?
RL95-2 NX7TU4NPT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFrTU5ZKSzVyPUG2MlM6PzhizszN NWn3cYM4W0GQR1XS
KNS-42 NFvQVI9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MX3JR|UxRTF4LkeyO|Qh|ryP M33CNXNCVkeHUh?=
RPMI-6666 NXfTenY4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHjtWVlKSzVyPUG2MlkzOTFizszN M3jaWnNCVkeHUh?=
SIG-M5 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFLnNohKSzVyPUG3MlE6ODNizszN NGXOdJNUSU6JRWK=
VA-ES-BJ NEXIU2ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1O1VWlEPTB;MUeuO|Q2OSEQvF2= NFHTSI1USU6JRWK=
MONO-MAC-6 MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHHBXphKSzVyPUG3Mlk{OTJizszN MnezV2FPT0WU
LAN-6 NFfkU2lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYTndGFrUUN3ME2xPE44PTV5IN88US=> Ml7mV2FPT0WU
A388 MWfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIL0V|NKSzVyPUG5MlMxPTlizszN MXjTRW5ITVJ?
SK-NEP-1 MoH4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGD2[oNKSzVyPUKwMlIyOzJizszN NHfDcpJUSU6JRWK=
TE-10 NWC5OXlJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIjvcGtKSzVyPUKwMlUzOjFizszN NHTvfZNUSU6JRWK=
HL-60 MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUjTWWF2UUN3ME2yNE46ODl7IN88US=> M1\BfHNCVkeHUh?=
MC116 MljmS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVv1[3plUUN3ME2yNU44OjJzIN88US=> NEDMfZpUSU6JRWK=
SW962 NIf5XJlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Ml61TWM2OD1{MT63PVE2KM7:TR?= M2XYOHNCVkeHUh?=
NOMO-1 M3PhOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlPwTWM2OD1{Mj62OVY1KM7:TR?= NGfI[ZFUSU6JRWK=
CTB-1 MlH1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX;OdY1yUUN3ME2yNk45PjdzIN88US=> NXKwTnJqW0GQR1XS
MRK-nu-1 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVXJR|UxRTJ{LkmwO|Qh|ryP M1HrcXNCVkeHUh?=
GR-ST Mn;QS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4\0UGlEPTB;MkOuO|Yh|ryP MkXnV2FPT0WU
HH M4\HOGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUjJR|UxRTJ2LkCwN{DPxE1? NIf3ZlhUSU6JRWK=
NCI-H1963 NUnNVmhPT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV\JR|UxRTJ2LkC3PFIh|ryP NGPEem1USU6JRWK=
QIMR-WIL MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFfJTYhKSzVyPUK0Mlg4PzJizszN NEfSUGpUSU6JRWK=
CGTH-W-1 NVrYOGFET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NESyOo1KSzVyPUK1MlA4OjNizszN M2fGVHNCVkeHUh?=
LP-1 MULHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXfJR|UxRTJ3Lk[1OVEh|ryP NHTkOVlUSU6JRWK=
NCI-H748 NIPhT|ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXvJR|UxRTJ4LkWxN|ch|ryP NFWwR2RUSU6JRWK=
PF-382 MonDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHfP[lFKSzVyPUK3MlIzOjNizszN NFrSd3RUSU6JRWK=
ATN-1 M2jFbmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYTCRXhwUUN3ME2yO{4{PzN{IN88US=> M3G3OHNCVkeHUh?=
L-540 M{PaWmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NELmfVlKSzVyPUK3MlY1PTlizszN M1LCT3NCVkeHUh?=
LXF-289 NVjLdmMxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGKyV3pKSzVyPUK3Mlc2OTlizszN MULTRW5ITVJ?
LS-513 NXvmdoJrT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mln1TWM2OD1{OD6xPFA4KM7:TR?= NEe4b|dUSU6JRWK=
NCI-H1581 M4ThWGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{XOVGlEPTB;M{CuN|k4PiEQvF2= NX7GPYg5W0GQR1XS
ES6 M3zLeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NET2SYRKSzVyPUOwMlY5QTlizszN M{DUN3NCVkeHUh?=
SW982 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmD0TWM2OD1|MD64OVY3KM7:TR?= NGft[XBUSU6JRWK=
DOHH-2 MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mmi0TWM2OD1|MT61PFk{KM7:TR?= M334cnNCVkeHUh?=
DB NEDoZ3ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVnJR|UxRTN|Lkm0N|Eh|ryP NVzLVlY1W0GQR1XS
MPP-89 NE[2XndIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoS3TWM2OD1|ND6xO|U3KM7:TR?= NVHmOVFzW0GQR1XS
LB831-BLC MljtS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2PmUmlEPTB;M{SuOVE5PCEQvF2= MWTTRW5ITVJ?
NB5 NH\ZVndIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NETrXI5KSzVyPUO0Mlg2OzVizszN MVfTRW5ITVJ?
GB-1 NEHlSYtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{PuO2lEPTB;M{WuNFQ3QSEQvF2= NITiVVhUSU6JRWK=
TE-15 NFfHZ3JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoPZTWM2OD1|NT6yNlM5KM7:TR?= MXPTRW5ITVJ?
LC4-1 M2Cw[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX7rNIx{UUN3ME2zOU4{QDR5IN88US=> NFzjU4RUSU6JRWK=
NCI-H747 NITBS4dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWP3WldPUUN3ME2zOk4yOzZ7IN88US=> MYHTRW5ITVJ?
NTERA-S-cl-D1 NVH3[3p4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHPnUIZKSzVyPUO4Mlc{PDdizszN NIPYRYVUSU6JRWK=
SK-MM-2 Mn;ZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIrpU2tKSzVyPUSwMlEyPDZizszN MkTvV2FPT0WU
TGW M3;xU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH7iRohKSzVyPUSxMlA2PjNizszN NEnMSJpUSU6JRWK=
ONS-76 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYXJR|UxRTR{LkS4PFMh|ryP NF\C[INUSU6JRWK=
CPC-N NIK4VZFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoiwTWM2OD12Mj65PVcyKM7:TR?= M2DLUnNCVkeHUh?=
ES4 NFG4OYxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NInlcWZKSzVyPUS0MlQyPTNizszN NWfkUWNxW0GQR1XS
Daudi MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnfXTWM2OD12NT6wPFI4KM7:TR?= M1S2WXNCVkeHUh?=
MOLT-4 NXzINHpiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NILaPZhKSzVyPUS1MlA5PTNizszN NHezWVRUSU6JRWK=
HT-144 NFzoVmpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHHXcplKSzVyPUS2MlczPiEQvF2= M3fOenNCVkeHUh?=
SW872 NH7ZSG1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmW4TWM2OD12OD6xPVM{KM7:TR?= NWT4c5o6W0GQR1XS
D-283MED MWXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEnhRZpKSzVyPUS4MlM2PDJizszN MXXTRW5ITVJ?
NCI-H2126 NXnSb2hGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M17LOGlEPTB;NEiuPFQ4PiEQvF2= Ml3DV2FPT0WU
NCI-SNU-16 NVThcVlUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIr1V2tKSzVyPUS5MlIyPDNizszN MlPTV2FPT0WU
CESS Mmm3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXHJR|UxRTR7LkWwPFgh|ryP MWLTRW5ITVJ?
A101D M1myOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlXVTWM2OD12OT65O|M3KM7:TR?= NUnkdZFZW0GQR1XS

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In vivo試験 In the GTL-16 model, PF-2341066 reveals the ability to cause marked regression of large established tumors (>600 mm3) in both the 50 mg/kg/day and 75 mg/kg/day treatment cohorts, with a 60% decrease in mean tumor volume over the 43-day administration schedule. In an another study, PF-2341066 displays the ability to completely inhibits GTL-16 tumor growth for >3 months, with only 1 of 12 mice exhibiting a significant increase in tumor growth over the 3-month treatment schedule at 50 mg/kg/day. In the NCI-H441 NSCLC model, a 43% decrease in mean tumor volume is observed at 50 mg/kg/day during the 38-day PF-2341066 administration cycle. In the Caki-1 RCC model, a 53% decrease in mean tumor volume is observed to be associated with decreased volume of each tumor by at least 30% at 50 mg/kg/day during the 33-day PF-2341066 administration cycle. PF-2341066 also reveals near-complete prevention of the growth of established tumors at 50 mg/kg/day in the U87MG glioblastoma or PC-3 prostate carcinoma xenograft models, with 97% or 84% inhibition on the final study day, respectively. In contrast, PF-2341066 p.o. given at 50 mg/kg/day does not significantly inhibit tumor growth in the MDA-MB-231 breast carcinoma model, or the DLD-1 colon carcinoma model. A significant dose-dependent reduction of CD31–positive endothelial cells is observed at 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day in GTL-16 tumors, indicating that inhibition of MVD shows a dose-dependent correlation to antitumor efficacy. PF-2341066 displays a significant dose-dependent reduction of human VEGFA and IL-8 plasma levels in both the GTL-16 and U87MG models. Marked inhibition of phosphorylated c-Met, Akt, Erk, PLCλ1, and STAT5 levels is observed in GTL-16 tumors following p.o. administration of PF-2341066.[1] P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts leads to dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 are observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function.[2] PF-2341066 prevents osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts are prevented by PF-2341066.[3] Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg PF-2341066 elicits tumor regression that is associated with a slow reduction in 18F-FDG uptake and decreases expression of the glucose transporter 1, GLUT-1.[4]
臨床試験 PF-2341066 is currently in a Phase III clinical trial in the treatment of non squamous lung cancer.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Cellular kinase phosphorylation ELISA assays Cells are seeded in 96-well plates in media supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free media [with 0.04% bovine serum albumin (BSA)] after 24 h. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 min. After incubation of cells with PF-2341066 for 1 h and/or appropriate ligands for the designated times, cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells. Subsequently, phosphorylation of selected protein kinases is assessed by a sandwich ELISA method using specific capture antibodies used to coat 96-well plates and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4°C overnight; (b) washed seven times in 1% Tween 20 in PBS; (c) incubated in a horseradish peroxidase–conjugated anti–total-phosphotyrosine (PY-20) antibody (1:500) for 30 min; (d) washed seven times again; (e) incubated in 3,3′,5,5′-tetramethyl benzidine peroxidase substrate to initiate a colorimetric reaction that is stopped by adding 0.09 N H2SO4; and (f) measured for absorbance in 450 nm using a spectrophotometer.

細胞アッセイ: [1]

細胞株 GTL-16 gastric carcinoma cells and T47D breast carcinoma cells
濃度 0-256 nM
反応時間 1 hour
実験の流れ Cells including GTL-16 gastric carcinoma cells and T47D breast carcinoma cells are seeded in 96-well plates in media supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free media [with 0.04% bovine serum albumin (BSA)] after 24 hours. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 minutes. After incubation of cells with PF-2341066 for 1 hour and/or appropriate ligands for the designated times, cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells. Subsequently, phosphorylation of selected protein kinases is assessed by a sandwich ELISA method using specific capture antibodies used to coat 96-well plates and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4 °C overnight; (b) washed seven times in 1% Tween 20 in PBS; (c) incubated in a horseradish peroxidase–conjugated anti–total-phosphotyrosine (PY-20) antibody (1:500) for 30 min; (d) washed seven times again; (e) incubated in 3,3,5,5-tetramethyl benzidine peroxidase substrate to initiate a colorimetric reaction that is stopped by adding 0.09 N H2SO4; and (f) measured for absorbance in 450 nm using a spectrophotometer.

動物実験: [1]

動物モデル Female or male nu/nu mice bearing NCI-H441,or DLD-1, or MDA-MB-231
製剤
投薬量 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day
投与方法 Administered via p.o.

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 Crizotinib (PF-02341066) SDF
分子量 450.34
化学式

C21H22Cl2FN5O

CAS No. 877399-52-5
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 9 mg/mL (19.98 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 5% DMSO+30% PEG 300+dd H2O 5mg/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 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

カスタマーフィードバック (8)


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Rating
Source Nat Med , 2011, 17, 1116-1120. Crizotinib (PF-02341066) purchased from Selleck
Method Western blot
Cell Lines RCT-E565 transplanted tumors
Concentrations 25 mg/kg/d, 50 mg/kg/d
Incubation Time 0-21 d
Results We then treated mice bearing RCT-E565 tumor transplants with PF02341066, a c-Met inhibitor currently in clinical development. PF02341066 abrogated both p-Akt and p-S6RP signals as well as tumor growth.

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Source Cancer Cell , 2011, 19, 679–690. Crizotinib (PF-02341066) purchased from Selleck
Method Cell Growth Inhibition Assay
Cell Lines Ba/F3 cells
Concentrations
Incubation Time 48 h
Results The sensitivities of L1196M-driven Ba/F3 cell clones to PF-02341066 were lower, closely resembling that of the Ba/F3 parental cells. The therapeutic indexes of CH5424802 and PF-02341066, the IC50 ratio of EML4-ALK L1196M-driven cell clones to the parental cells, were 7- to 12-fold and 1- to 2-fold.

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Source Cancer Cell , 2011, 19, 679–690. Crizotinib (PF-02341066) purchased from Selleck
Method Immunoblot analysis, Tumor growth inhibition Assay
Cell Lines xenograft models
Concentrations 100 mg/kg
Incubation Time 8 days
Results We showed that administration of CH5424802 led to significant tumor regression against both native EML4-ALK- and L1196M-driven tumors. On the other hand, PF-02341066 (100 mg/kg) resulted in no significant tumor growth inhibition against L1196M-driven tumors. Furthermore, we confirmed that phospho-STAT3, one of the downstream targets of ALK, was abolished in both tumors that were treated with CH5424802.

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Source J Biomol Screen , 2011, 16, 141-154. Crizotinib (PF-02341066) purchased from Selleck
Method VimPro-Fluc-MDA-MB-231 spheroid viability, Western blot
Cell Lines MDA-MB-231 spheroids
Concentrations
Incubation Time
Results When Vimpro-Fluc downregulation reaches ≥70%, then downregulation of vimentin protein expression is more pronounced. of the modulators tested—U0126, dasatinib,axitinib, and pF2341066-all downregulated Vimpro-Fluc activity by ≥70%, which correlated with a significant down-reglation of vimentin protein expression. Finally, dose-response curves were generated with both U0126 (iC50 = 2.5 µM) and axitinib (iC50 = 0.25 µM), demonstrating that these small molecules modulate Vimpro-Fluc activity in a dose-dependent manner, indicating that their respective target(s) and signaling pathways play a significant role in maintaining vimentin expression and possibly mesenchymal homeostasis (Fig. B)

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Rating
Source J Biomol Screen , 2011, 16, 141-154. Crizotinib (PF-02341066) purchased from Selleck
Method Secondary assay
Cell Lines MDA-MB-231 spheroids
Concentrations 10 µM
Incubation Time
Results U0126, pF2341066, axitinib, and pKC412 caused significant inhibition of the invasive potential of Mda-Mb-231 spheroids. Conversely, dasatinib, a potent inhibitor of vimentin gene expression, did not significantly alter the invasive potential of Mda-Mb-231 spheroids.

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Rating
Source Int J Proteomics , 2011, 2011, 215496. Crizotinib (PF-02341066) purchased from Selleck
Method CEER assay
Cell Lines H1993 cell line
Concentrations 0-10 μM
Incubation Time 4 h
Results In the c-MET amplified cell line H1993, activation of this pathway was blocked by the treatment with PF-2341066, a c-MET kinase inhibitor.

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Rating
Source Int J Proteomics, 2011, 2011, Article ID 215496. Crizotinib (PF-02341066) purchased from Selleck
Method Nikon inverted-phase microscope
Cell Lines lung tumor cell lines
Concentrations 0.1/1 µM
Incubation Time two weeks
Results Large colony formation of H1993 cells, whose proliferation in tissue culture was potently blocked by treatment with the c-MET kinase inhibitor PF-2341066, was also inhibited by treatment with the same inhibitor.

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Rating
Source Dr. Zhang of Tianjin Medical University. Crizotinib (PF-02341066) purchased from Selleck
Method Western blot
Cell Lines MDA-MB-231 cell line
Concentrations 0-100 nM
Incubation Time
Results

文献中の引用 (65)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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