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

高品質保証

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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 NWX1U45TS3m2b4TvfIlkKEG|c3H5 NXS3PHlzPDhiaB?= NHvm[3dFVVOR NWLQV5lmS3m2b4TvfIlkcXS7IHHnZYlve3RibX;1d4UhSkGIMzDj[YxteyCneIDy[ZN{cW6pIFHMT{BHOTF5NFygcZV1[W62IHPv[ZhxemW|c3nu[{BGVUx2IIfpeIghUUN3MDDv[kAxNjZ{IN88US=> MkfmNlE2PzJ3OEm=
BAF3 MYrDfZRwfG:6aXOgRZN{[Xl? M2HUU|Q5KGh? MmWySG1UVw>? MWLDfZRwfG:6aXPpeJkh[WejaX7zeEBud3W|ZTDCRWY{KGOnbHzzJIV5eHKnc4PpcochSUyNIFyxNVk3VSCvdYThcpQh[2:neIDy[ZN{cW6pIFXNUFQhf2m2aDDJR|UxKG:oIEKuNkDPxE1? M{HkOFIyPTd{NUi5
BAF3 MlLBR5l1d3SxeHnjJGF{e2G7 MUi0PEBp MUPEUXNQ NWTMT3Q4S3m2b4TvfIlkcXS7IHHnZYlve3RibX;1d4UhSkGIMzDj[YxteyCneIDy[ZN{cW6pIFXNUFQuSUyNIIfpeIghUUN3MDDv[kAxNjJ6IN88US=> M{HWVVIyPTd{NUi5
Kelly M4XJdmN6fG:2b4jpZ{BCe3OjeR?= NV\kZ3YyTE2VTx?= NXnkd5FHS3m2b4TvfIlkcXS7IHHnZYlve3RiaIXtZY4hU2WubImgZ4VtdHNiZYjwdoV{e2mwZzDBUGshTjFzN{TMJI12fGGwdDD3bZRpKEmFNUCgc4YhOC52MjFOwG0> MWWyNVU4OjV6OR?=
SH-SY5Y M4DteGN6fG:2b4jpZ{BCe3OjeR?= NFzHZY5FVVOR NE\uXlhEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBUUC2VWUXZJINmdGy|IHX4dJJme3OrbnegRWxMKEZzMUe0UEBufXSjboSge4l1cCCLQ{WwJI9nKDBwNUOg{txO NUnXO5ptOjF3N{K1PFk>
SMS-KCN NIr3fVhEgXSxdH;4bYMhSXO|YYm= M4DSTWROW09? M3izTWN6fG:2b4jpZ4l1gSCjZ3HpcpN1KGi3bXHuJHNOWy2NQ16gZ4VtdHNiZYjwdoV{e2mwZzDBUGshWjF{N{XRJI12fGGwdDD3bZRpKEmFNUCgc4YhOC57MTFOwG0> MW[yNVU4OjV6OR?=
BAF3 NI\4dINEgXSxdH;4bYMhSXO|YYm= MmrROFghcA>? M2jTXGROW09? MVrDfZRwfG:6aXPpeJkh[WejaX7zeEBud3W|ZTDCRWY{KGOnbHzzJIV5eHKnc4PpcochXGWuLVHMT{B4cXSqIFnDOVAhd2ZiMD6xPUDPxE1? MWiyNVU4OjV6OR?=
3T3 NXnOblEzTnWwY4Tpc44hSXO|YYm= MXuxJIg> NXPMXoFrTE2VTx?= MXTJcohq[mm2aX;uJI9nKFKRTjDhd5Nme3OnZDDhd{Boem:5dHig[oFkfG:{LXnu[JVk\WRiYYX0c5Bpd3OyaH;yfYxifGmxbjD3bZRpKEmFNUCgc4YhOC5yODFOwG0> M2fC[|IyQDF{NEG0
3T3-E Mn;VSpVv[3Srb36gRZN{[Xl? M3;UclEhcA>? M4Dp[mROW09? NYCzbVRyUW6qaXLpeIlwdiCxZjDUTWUzKGG|c3Xzd4VlKGe{b4f0bEBn[WO2b4KtbY5lfWOnZDDheZRweGixc4Doc5J6dGG2aX;uJJdqfGhiSVO1NEBw\iByLkS0PEDPxE1? M4\Zb|IyQDF{NEG0
A549 MVrLbY5ie2ViQYPzZZk> NVj0dFV5OSCq MmPlSG1UVw>? NILkOWhKdmirYnn0bY9vKG:oIHj1cYFvKHKnY3;tZolv[W62IHOtUWVVKGurbnHz[UBmgHC{ZYPz[YQh[XO|ZYPz[YQh[XNiaX7obYJqfGmxbjDv[kBJT0ZvaX7keYNm\CCjdYTvdIhwe3Cqb4L5cIF1cW:wIIfpeIghUUN3MDDv[kAxNjByODFOwG0> MmmzNlE5OTJ2MUS=
BAF3-BCL NUPkZXA6TnWwY4Tpc44hSXO|YYm= NFzaT2kyKGh? Mnn3SG1UVw>? NEPwRZdKdmirYnn0bY9vKG:oIFHCUEBie3Onc4Pl[EBieyCpcn;3eIgh\mGldH;yMYlv\HWlZXSgZZV1d3Cqb4PwbI9zgWyjdHnvckB4cXSqIFnDOVAhd2ZiMT6xOVkh|ryP NYfXWYl7OjF6MUK0NVQ>
HEK293 NX3yVlIzTnWwY4Tpc44hSXO|YYm= NUfIe2JLOSCq NH7PZZFFVVOR NID5T5FKdmirYnn0bY9vKG:oIFHYUEBie3Onc4Pl[EBieyCpcn;3eIgh\mGldH;yMYlv\HWlZXSgZZV1d3Cqb4PwbI9zgWyjdHnvckB4cXSqIFnDOVAhd2ZiMD6yPVQh|ryP MUWyNVgyOjRzNB?=
HEK293 NFraeJpHfW6ldHnvckBCe3OjeR?= M1rwTFEhcA>? MWDEUXNQ M{TnbGlvcGmkaYTpc44hd2ZiSWKgZZN{\XO|ZXSgZZMh\3Kxd4ToJIZi[3Sxcj3pcoR2[2WmIHH1eI9xcG:|cHjvdplt[XSrb36ge4l1cCCLQ{WwJI9nKDJwOEi3JO69VQ>? MWCyNVgyOjRzNB?=
Jurkat M2L4cmZ2dmO2aX;uJGF{e2G7 M3SwRVEhcA>? NVj5S2pyTE2VTx?= NHj6eIxKdmirYnn0bY9vKG:oIFzDT{Bie3Onc4Pl[EBieyCpcn;3eIgh\mGldH;yMYlv\HWlZXSgZZV1d3Cqb4PwbI9zgWyjdHnvckB4cXSqIFnDOVAhd2ZiMj63OFEh|ryP NUXBSY56OjF6MUK0NVQ>
KARPAS299 MVfLbY5ie2ViQYPzZZk> MnLkNUBp NXPMUm5xTE2VTx?= MVjJcohq[mm2aX;uJI9nKEGOSzDhd5Nme3OnZDDhd{Boem:5dHig[oFkfG:{LXnu[JVk\WRiYYX0c5Bpd3OyaH;yfYxifGmxbjD3bZRpKEmFNUCgc4YhOC5yMjFOwG0> NF;qeHUzOThzMkSxOC=>
PAE NFnvRodHfW6ldHnvckBCe3OjeR?= MUexJIg> MXfEUXNQ MXfJcohq[mm2aX;uJI9nKFSUS1KgZZN{\XO|ZXSgZZMh\3Kxd4ToJIZi[3Sxcj3pcoR2[2WmIHH1eI9xcG:|cHjvdplt[XSrb36ge4l1cCCLQ{WwJI9nKDBwM{m5JO69VQ>? NUjWdJYxOjF6MUK0NVQ>
BAF3 MVLGeY5kfGmxbjDBd5NigQ>? M4T3elIuOyCm NULaNWxyTE2VTx?= M2e1XmlvcGmkaYTpc44hd2ZiVFXMMYZ2e2WmIHnud5VtcW5icnXj[ZB1d3JiZYjwdoV{e2WmIIfpeIghUUN3MDDv[kAyNjZ2MzFOwG0> NF24V4szOzd2MkK1Ni=>
KARPAS299 MUDDfZRwfG:6aXOgRZN{[Xl? MoTQNk0{KGR? NX\O[G9tTE2VTx?= MX\JR|UxRTBwME[0NkDPxE1? MkX1NlM4PDJ{NUK=
EBC1 Ml;hS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGD5blU4OiCq MXnEUXNQ NFXmTVZKSzVyPUCuNFI{KM7:TR?= NX;BeGROOjN7OUOzNlg>
HCT116 NEnnfWdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2i4SFczKGh? NUnLbWxWTE2VTx?= M{PlfWlEPTB;MUSuPFIh|ryP M1KyeFI{QTl|M{K4
MCF7 MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlnLO|IhcA>? M3j0NGROW09? NUDOO4szUUN3ME25MlU5KM7:TR?= NX7KSYlXOjN7OUOzNlg>
MDA-MB-231 NYrrfol2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXW3NkBp NH7zO|BFVVOR MoTHTWM2OD1zMD64JO69VQ>? NFe5fmIzOzl7M{OyPC=>
MKN45 NV\IZ2szT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWL4ZVVQPzJiaB?= M{TQ[mROW09? MWfJR|UxRTBwMEGzJO69VQ>? NWr3XGhvOjN7OUOzNlg>
NCI-H441 MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEfzeFY4OiCq M3O2T2ROW09? NFnUT|ZKSzVyPUG3MlI2KM7:TR?= NXjQVo41OjN7OUOzNlg>
NCI-H661 MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3SwT|czKGh? M2jYbWROW09? NGj6VIVKSzVyPUGxMlQ4KM7:TR?= MnnWNlM6QTN|Mki=
SK-MEL-28 NUjIdHVoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnvZO|IhcA>? M4\ZeWROW09? Mn7MTWM2OD1zMD65O{DPxE1? M3z0OlI{QTl|M{K4
SKOV3 NUHIZ3NET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1LuSFczKGh? NXjFdHJSTE2VTx?= MVzJR|UxRTF{Lki1JO69VQ>? MXeyN|k6OzN{OB?=
SNU5 NEjtUGpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmXUO|IhcA>? Mm\GSG1UVw>? M3LIO2lEPTB;MD6wNVYh|ryP MnzaNlM6QTN|Mki=
NCI-H2228 M4XhcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGTmXFA4OiCq M3nQfmROW09? NXLmOVV4UW6qaXLpeIlwdiCxZjDBUGsu\nW|aX;uJIRzcX[nbjDj[YxtKHC{b3zp[oVz[XSrb36ge4l1cCCLQ{WwJI9nKDBwMUG4JO69VQ>? NXSz[phNOjR2M{K5NFk>
NCI-H3122 MUjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYO3NkBp MU\EUXNQ MnL2TY5pcWKrdHnvckBw\iCDTFut[pV{cW:wIHTybZZmdiClZXzsJJBzd2yrZnXyZZRqd25id3n0bEBKSzVyIH;mJFAvOTB6IN88US=> NVS5TYQxOjR2M{K5NFk>
NCI-H3122 M2\oTmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUfUNm9uPzJiaB?= NHfjVodFVVOR MWrJcohq[mm2aX;uJI9nKEGOSz3meZNqd25iZILpeoVvKGOnbHygdJJwdGmoZYLheIlwdiCrbjDoeY1idiCQQ1mtTFMyOjJiY3XscJMhcGG{Yn;ybY5oKEGOSzDHNVI3QUFibYX0ZY51KHerdHigTWM2OCCxZjCwMlYzOyEQvF2= NFTtXnIzPDR|MkmwPS=>
NCI-H3122 MmnjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlzIO|IhcA>? MV7EUXNQ NIXIdIxKdmirYnn0bY9vKG:oIFHMT{1nfXOrb36g[JJqfmWwIHPlcIwheHKxbHnm[ZJifGmxbjDpckBpfW2jbjDOR2kuUDNzMkKgZ4VtdHNiaHHyZo9zcW6pIFHMT{BNOTF7Nl2gcZV1[W62IIfpeIghUUN3MDDv[kAxNjh|ODFOwG0> NF3BTIgzPDR|MkmwPS=>
NIH-3T3 NG\hfXBMcW6jc3WgRZN{[Xl? NEO0SIcyKGh? Mm\CSG1UVw>? NGH6[3JKdmirYnn0bY9vKG:oIHj1cYFvKHerbHSgeJlx\SCHTVy0MYZ2e2WmIFHMT{BmgHC{ZYPz[YQh[XO|ZYPz[YQh[XNicHjvd5Bpd3K7bHH0[YQhSUyNIHzleoVtKHerdHigTWM2OCCxZjCwMlA5KM7:TR?= NXj2foRJOjR2M{K5NFk>
NIH-3T3 NHHTNGJMcW6jc3WgRZN{[Xl? Mn\GNUBp NXG3fnpPTE2VTx?= NWLYWWxJUW6qaXLpeIlwdiCxZjDoeY1idiCHTVy0MYZ2e2WmIFHMT{BIOTJ4OVGgcZV1[W62IHX4dJJme3OnZDDhd5Nme3OnZDDhd{BxcG:|cHjvMWFNUyCuZY\lcEB4cXSqIFnDOVAhd2ZiMD62NFUh|ryP MY[yOFQ{OjlyOR?=
NIH-3T3 MoTOT4lv[XOnIFHzd4F6 NFLBdXoyKGh? M{XifGROW09? M1rtT2lvcGmkaYTpc44hd2ZiaIXtZY4hTU2OND3meZNm\CCDTFugV|EzOD[\IH31eIFvfCCneIDy[ZN{\WRiYYPz[ZN{\WRiYYOgdIhwe3Cqbz3BUGshdGW4ZXyge4l1cCCLQ{WwJI9nKDBwNkK2JO69VQ>? NEXqeZAzPDR|MkmwPS=>
NIH-3T3 MUjLbY5ie2ViQYPzZZk> M3X1T|EhcA>? NGT3NI9FVVOR MnmxTY5pcWKrdHnvckBw\iCqdX3hckBGVUx2LX\1d4VlKEGOSzDMNVE6Pk1ibYX0ZY51KGW6cILld5Nm\CCjc4Pld5Nm\CCjczDwbI9{eGixLVHMT{Bt\X[nbDD3bZRpKEmFNUCgc4YhOC56NEOg{txO NHW3fWIzPDR|MkmwPS=>
NIH-3T3 Mlq5T4lv[XOnIFHzd4F6 MWKxJIg> NVm4fJpvTE2VTx?= MU\Jcohq[mm2aX;uJI9nKGi3bXHuJGVOVDRvZoXz[YQhSUyNIFyxNVUzWiCvdYThcpQh\XiycnXzd4VlKGG|c3Xzd4VlKGG|IIDoc5NxcG9vQVzLJIxmfmWuIIfpeIghUUN3MDDv[kAyNjB{NjFOwG0> Mlv4NlQ1OzJ7MEm=
BAF3 MlHLSpVv[3Srb36gRZN{[Xl? M1\LNFczKGh? NV3ZdFFFTE2VTx?= MnPGTY5pcWKrdHnvckBw\iCQUF2vRWxMKHS{YX7z[oVkfGWmIHHzd4V{e2WmIHHzJINmdGxiZ4Lve5RpKGmwaHnibZRqd25id3n0bEBKSzVyIH;mJFAvODVzIN88US=> NEDaWm0zPDR4OE[zNi=>
BAF3 M1j6TGN6fG:2b4jpZ{BCe3OjeR?= M{DHXlczKGh? NIroVXNFVVOR MlfiTWM2OD1yLkm4JO69VQ>? MXmyOFQ3QDZ|Mh?=
NIH-3T3 NEfNSZZMcW6jc3WgRZN{[Xl? NFnWV5kyKGh? MVHJcohq[mm2aX;uJI9nKGi3bXHuJGVOVDRvZoXz[YQhSUyNIF[xNVc1VCCvdYThcpQh\XiycnXzd4VlKGG|c3Xzd4VlKGG|IIDoc5NxcG9vQVzLJIxmfmWuIIfpeIghUUN3MDDv[kAxNjF4NTFOwG0> NYrKXIFXOjR6MUmxNVY>
NIH-3T3 NH7ue2lMcW6jc3WgRZN{[Xl? MoDGNUBp NIrHd|FKdmirYnn0bY9vKG:oIHj1cYFvKEWPTESt[pV{\WRiQVzLJGMyOTV4WTDteZRidnRiZYjwdoV{e2WmIHHzd4V{e2WmIHHzJJBpd3OyaH:tRWxMKGyndnXsJJdqfGhiSVO1NEBw\iByLkS3PEDPxE1? NGLyPJIzPDhzOUGxOi=>
NIH-3T3 NEH0c2NMcW6jc3WgRZN{[Xl? MmTINUBp NWTMZYViUW6qaXLpeIlwdiCxZjDoeY1idiCHTVy0MYZ2e2WmIFHMT{BIOTJyMmKgcZV1[W62IHX4dJJme3OnZDDhd5Nme3OnZDDhd{BxcG:|cHjvMWFNUyCuZY\lcEB4cXSqIFnDOVAhd2ZiMT6xOFgh|ryP NGfVNWszPDhzOUGxOi=>
NIH-3T3 NIrn[HJMcW6jc3WgRZN{[Xl? MorONUBp NHTnTGhKdmirYnn0bY9vKG:oIHj1cYFvKEWPTESt[pV{\WRiQVzLJFEyPTGWaX7zJI12fGGwdDDlfJBz\XO|ZXSgZZN{\XO|ZXSgZZMheGixc4Doc{1CVEtibHX2[Ywhf2m2aDDJR|UxKG:oIEOuNFM6KM7:TR?= NF61foEzPDhzOUGxOi=>
KARPAS299 NIfNVnJMcW6jc3WgRZN{[Xl? NU\XOJBkQTBibXnu NXfMcXBJTE2VTx?= NX;kR4ZEUW6qaXLpeIlwdiCxZjDOVG0u\nW|ZXSgRWxMKHCqb4PwbI9zgWyjdHnvckBmgHC{ZYPz[YQhf2m2aDDJR|UxKG:oIECuNVEh|ryP M4LjSFI1QTByN{Ww
MKN 45 NV6zfJc4U2mwYYPlJGF{e2G7 MY[xJIg> MUTEUXNQ NVH5O4ZFUW6qaXLpeIlwdiCxZjDjMW1mfCCyaH;zdIhwenmuYYTpc44hf2m2aDDJR|UxKG:oIECuNFIh|ryP NG\1OnMzPDlyMEe1NC=>
A549 MoPoR5l1d3SxeHnjJGF{e2G7 MYK0PEBp MkXtSG1UVw>? NE\rPXdKSzVyIH;mJFQvODh2IN88US=> MWiyOFkxODh|MB?=
NCI-H1975 NGTkR4xEgXSxdH;4bYMhSXO|YYm= M3XWRlQ5KGh? MoW2SG1UVw>? M33xbGlEPTBib3[gO{42PTFizszN NV\nV2IyOjR7MEC4N|A>
NCI-H1993 NXPEPIlPS3m2b4TvfIlkKEG|c3H5 NYDOT2VFPDhiaB?= NWGyVFJ2TE2VTx?= MkfFTWM2OCCxZjCwMlA3OSEQvF2= NH\zO4YzPDlyMEizNC=>
NCI-H1993 MmX6RZBwfG:|aYOgRZN{[Xl? NUWybFY2OSEQvF2= MnHKNlQhcA>? MY\EUXNQ MXzkc4V{KG6xdDDpcoR2[2ViYYDvdJRwe2m| NYH4NIxSOjR7MEC4N|A>
NIH-3T3 M2nMRmN6fG:2b4jpZ{BCe3OjeR?= MonROFghcA>? NF3lfXJFVVOR MmTyTWM2OCCxZjCwMlM3PCEQvF2= M{XhW|I1QTByOEOw
EBC1 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWG3NkBp NYLqfnNuTE2VTx?= MWDJR|UxKG:oIECuNFA3QSEQvF2= NV\EUYhEOjR7MEC4N|E>
KARPAS299 NVj5d|RiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnLtO|IhcA>? M3nWbmROW09? MYPJR|UxKG:oIECuNkDPxE1? NFzJeYczPDlyMEizNS=>
NB1 NUHkeJRMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEjUU2lKSzVyPUmxMlk5KG6P NXLpbG5yW0GQR1XS
NCI-SNU-5 NFq2XFlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4\RdGlEPTB;MUC1Mlc2KG6P NHrLUYVUSU6JRWK=
SR Mo\wS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmrSTWM2OD1zMk[uN|Ehdk1? M{DXPXNCVkeHUh?=
SF539 MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGDyeJdKSzVyPUKwOE4zPCCwTR?= M4CwdnNCVkeHUh?=
SU-DHL-1 NEfSRmxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3jqVWlEPTB;M{O2MlgzKG6P NGHUN3hUSU6JRWK=
SCC-3 MorrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWDaXFBmUUN3ME2zOVYvPzZibl2= M2rsb3NCVkeHUh?=
DEL MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mlr0TWM2OD1|NkmuPUBvVQ>? NVKzbWcyW0GQR1XS
CTV-1 NIXsbFVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NG[4RYdKSzVyPUW5Ok41QCCwTR?= MUnTRW5ITVJ?
EM-2 MmfsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVj0S2ZWUUN3ME22NFEvOzRibl2= MVjTRW5ITVJ?
MHH-CALL-2 M{XBWWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4[0SWlEPTB;NkiyMlU4KG6P MYXTRW5ITVJ?
KM12 NVXIZoxDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVv5c5A4UUN3ME23NFYvQSCwTR?= MYfTRW5ITVJ?
KINGS-1 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWHYTVFZUUN3ME23OFkvPzVibl2= MkP6V2FPT0WU
MEG-01 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWjPVJBDUUN3ME24OVcvPjZibl2= M4PvS3NCVkeHUh?=
BV-173 NXXYe4tXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXnlOpZpUUN3ME2xMlA2QTl5IN88US=> NVn2bnB3W0GQR1XS
LAMA-84 MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3Oz[2lEPTB;MT6zPFI5OiEQvF2= NGfu[YtUSU6JRWK=
KARPAS-299 NVfaOYt1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2TVb2lEPTB;MT60NFg3OSEQvF2= M{LZR3NCVkeHUh?=
K-562 NUj5V486T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYDab3puUUN3ME2xMlczOjZ7IN88US=> NVfnRm1jW0GQR1XS
SK-LMS-1 M1;sSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmrUTWM2OD1zLke2PFY4KM7:TR?= NH;XS2NUSU6JRWK=
MOLT-16 NUTXTGtsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVTJR|UxRTFwOUW1O|Uh|ryP M4\2S3NCVkeHUh?=
CMK M2T3Zmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlvrTWM2OD1zLkm2NVU6KM7:TR?= Ml3QV2FPT0WU
ST486 NE\0PZdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHvG[41KSzVyPUKuOFMxPzNizszN M{DnNXNCVkeHUh?=
CI-1 NYTIN|QxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVXG[4RSUUN3ME2yMlQ6PjV7IN88US=> NUHWfIJwW0GQR1XS
KP-N-RT-BM-1 MkTDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1nYO2lEPTB;Mj63NFEzOiEQvF2= MXTTRW5ITVJ?
ALL-PO MmrKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX;JR|UxRTNwMUiyNFch|ryP NF7QSnNUSU6JRWK=
KS-1 Mlq2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWLJR|UxRTNwMkGyNlUh|ryP NVK3eFBpW0GQR1XS
Becker MlXuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2CxVWlEPTB;ND6yN|k{KM7:TR?= MVrTRW5ITVJ?
GDM-1 M4X0Smdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUDJR|UxRTRwMkS2NVch|ryP M3PScHNCVkeHUh?=
BC-1 MWfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnfiTWM2OD12LkS5Nlc4KM7:TR?= MVLTRW5ITVJ?
NB14 MkfSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFTLfnlKSzVyPUSuPFM2OjRizszN Mn7iV2FPT0WU
NOS-1 M{jMN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVfJR|UxRTVwM{O4O|Qh|ryP NFXRPYZUSU6JRWK=
MZ1-PC MnrrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mn30TWM2OD13LkiyNVUyKM7:TR?= M4jMNnNCVkeHUh?=
A498 NVLJUXdzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVjJR|UxRTZwMEi0O|Mh|ryP NWCzO5RmW0GQR1XS
EW-16 Mm[1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlHETWM2OD14LkO3O|c{KM7:TR?= MnfXV2FPT0WU
NALM-6 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXyzXnJIUUN3ME22MlY5Ozh5IN88US=> Mn\KV2FPT0WU
EB-3 NEe4R2lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MorLTWM2OD15LkC3NlM{KM7:TR?= M2[1[nNCVkeHUh?=
697 NV\zPFJST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{nMUWlEPTB;OT6yOFMzQSEQvF2= NWjyRmZUW0GQR1XS
Ramos-2G6-4C10 MlTOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnjwTWM2OD17LkW5PFQzKM7:TR?= NWPlTXQyW0GQR1XS
KNS-81-FD MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUDCO5RyUUN3ME25MlY6PjV|IN88US=> NFjMWWxUSU6JRWK=
HUTU-80 NEi5XYlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXjaRmI{UUN3ME25Mlc1PjR{IN88US=> NHjaXFNUSU6JRWK=
LS-411N M2fCR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MojVTWM2OD1zMD6wOVY4KM7:TR?= MYLTRW5ITVJ?
RPMI-8402 NEn0SmxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFLE[4pKSzVyPUGwMlEyPiEQvF2= M4Lhe3NCVkeHUh?=
KU812 M3rxV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1uzcmlEPTB;MUCuNlk6OSEQvF2= NHTJW3RUSU6JRWK=
EW-1 MmewS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoPhTWM2OD1zMD60OFI2KM7:TR?= NFP5eG5USU6JRWK=
HC-1 NHXCWHhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFTpeI9KSzVyPUGwMlQ5PDRizszN NF7yZmlUSU6JRWK=
NB69 NEH6b3lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVfJR|UxRTFyLkWwOFMh|ryP NU\aPYVYW0GQR1XS
MFH-ino NFXJVHdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFHPTnlKSzVyPUGwMlg{ODNizszN M{P3enNCVkeHUh?=
CCRF-CEM MmTMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWTJR|UxRTFzLkW5O{DPxE1? MXrTRW5ITVJ?
SK-N-DZ Mmm5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGTYXHRKSzVyPUGyMlA1OzZizszN M4XwZ3NCVkeHUh?=
NCI-H720 MnTVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVHYemlKUUN3ME2xNk4yPzB3IN88US=> MmWwV2FPT0WU
HCC1187 M4fPOGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M33pO2lEPTB;MUKuNlA1OSEQvF2= MYfTRW5ITVJ?
IST-SL2 NFLlOWdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MWXJR|UxRTF{LkS4O|Ih|ryP MmLyV2FPT0WU
KE-37 NFHKOZZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NX:4[ZpnUUN3ME2xNk44QTZ4IN88US=> M3HiSXNCVkeHUh?=
HCC1599 M3KzOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MojuTWM2OD1zMj65NFY6KM7:TR?= MkLpV2FPT0WU
A4-Fuk NULzVWptT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVrJR|UxRTF{Lkm1PFYh|ryP NUHJUJhGW0GQR1XS
NKM-1 MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFjnS2pKSzVyPUGzMlI6OjVizszN MUTTRW5ITVJ?
BE-13 NV:5OolXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M37pO2lEPTB;MUOuO|k5QSEQvF2= MkLvV2FPT0WU
MV-4-11 MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUXJR|UxRTF2LkCzNlQh|ryP MVrTRW5ITVJ?
OPM-2 M2rsRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{e5[2lEPTB;MUSuOFA5PSEQvF2= NV3JZ3lGW0GQR1XS
KARPAS-422 MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{S4b2lEPTB;MUSuOVEzPiEQvF2= MULTRW5ITVJ?
RPMI-8226 NYDLOHZ6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYj3ZnRuUUN3ME2xOE45QTF3IN88US=> MXPTRW5ITVJ?
KARPAS-45 MmDpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXXmSY97UUN3ME2xOU44PzF4IN88US=> M3;RfXNCVkeHUh?=
SK-PN-DW M{fCbWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoDWTWM2OD1zNT64OlMyKM7:TR?= NVGyZpJCW0GQR1XS
LC-2 NHuzO2VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{L1emlEPTB;MU[uNVUxPiEQvF2= NIe4NpNUSU6JRWK=
NCI-H1648 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFmwSZlKSzVyPUG2MlI2PCEQvF2= NFn1[mxUSU6JRWK=
RL95-2 NVXOVGVzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYPJR|UxRTF4LkO5O|gh|ryP MkjzV2FPT0WU
KNS-42 MmjhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmHxTWM2OD1zNj63Nlc1KM7:TR?= NWKyUGJNW0GQR1XS
RPMI-6666 NWm1ZXVET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXHBUoFwUUN3ME2xOk46OjFzIN88US=> NWrTZmttW0GQR1XS
SIG-M5 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFvEPIlKSzVyPUG3MlE6ODNizszN NGW2e|dUSU6JRWK=
VA-ES-BJ NWG5bopGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmHZTWM2OD1zNz63OFUyKM7:TR?= NVr1UVBZW0GQR1XS
MONO-MAC-6 MmrkS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2rYb2lEPTB;MUeuPVMyOiEQvF2= NILOcHhUSU6JRWK=
LAN-6 NH2xOZFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEDCbYRKSzVyPUG4Mlc2PTdizszN MXXTRW5ITVJ?
A388 MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NE[wZ4JKSzVyPUG5MlMxPTlizszN MYDTRW5ITVJ?
SK-NEP-1 NEjFbYpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3W1fWlEPTB;MkCuNlE{OiEQvF2= MVnTRW5ITVJ?
TE-10 NUXrd3BkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NELpeIdKSzVyPUKwMlUzOjFizszN MUDTRW5ITVJ?
HL-60 NWT2OJRFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUDJR|UxRTJyLkmwPVkh|ryP MUHTRW5ITVJ?
MC116 M3fvZ2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MliyTWM2OD1{MT63NlIyKM7:TR?= MofxV2FPT0WU
SW962 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{flXmlEPTB;MkGuO|kyPSEQvF2= NYPKPZdWW0GQR1XS
NOMO-1 M3LkT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHH5SXZKSzVyPUKyMlY2PjRizszN MUXTRW5ITVJ?
CTB-1 M2np[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUT2Soh2UUN3ME2yNk45PjdzIN88US=> M4PIcHNCVkeHUh?=
MRK-nu-1 NWXBW3ZFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVzIOHF3UUN3ME2yNk46ODd2IN88US=> NVrqXWVYW0GQR1XS
GR-ST M4C1c2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NU\6NWk{UUN3ME2yN{44PiEQvF2= MnLGV2FPT0WU
HH MorVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MV7JR|UxRTJ2LkCwN{DPxE1? NF7GRm9USU6JRWK=
NCI-H1963 NY\X[4U2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnnITWM2OD1{ND6wO|gzKM7:TR?= MlHpV2FPT0WU
QIMR-WIL NXPDUJVvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mlz5TWM2OD1{ND64O|czKM7:TR?= M1XpOXNCVkeHUh?=
CGTH-W-1 NEXifZhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnzjTWM2OD1{NT6wO|I{KM7:TR?= NYXvXoFyW0GQR1XS
LP-1 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MljjTWM2OD1{NT62OVUyKM7:TR?= MYnTRW5ITVJ?
NCI-H748 M4fKUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF\3OopKSzVyPUK2MlUyOzdizszN NEe4dVZUSU6JRWK=
PF-382 M3e1XGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Ml65TWM2OD1{Nz6yNlI{KM7:TR?= NFfSSlBUSU6JRWK=
ATN-1 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NE\LV4VKSzVyPUK3MlM4OzJizszN MkHIV2FPT0WU
L-540 M{XKUGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnrPTWM2OD1{Nz62OFU6KM7:TR?= M{iwSXNCVkeHUh?=
LXF-289 NGO2W|ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHvtbHlKSzVyPUK3Mlc2OTlizszN NULDZY1UW0GQR1XS
LS-513 NH;rUYJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MUfJR|UxRTJ6LkG4NFch|ryP M1n0NHNCVkeHUh?=
NCI-H1581 M4\KPWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2rZemlEPTB;M{CuN|k4PiEQvF2= MUjTRW5ITVJ?
ES6 NYTKWWh{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVyycI1ZUUN3ME2zNE43QDl7IN88US=> MnrrV2FPT0WU
SW982 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnP1TWM2OD1|MD64OVY3KM7:TR?= NIjKOHpUSU6JRWK=
DOHH-2 NGn5O3BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYj2W5VsUUN3ME2zNU42QDl|IN88US=> NGjYUZVUSU6JRWK=
DB NUXWTm5tT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlTnTWM2OD1|Mz65OFMyKM7:TR?= Mn;2V2FPT0WU
MPP-89 NHPHcJlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVvT[IZGUUN3ME2zOE4yPzV4IN88US=> M2ftWnNCVkeHUh?=
LB831-BLC MnrLS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWHLT2N7UUN3ME2zOE42OTh2IN88US=> MVPTRW5ITVJ?
NB5 NF:xPYtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkTWTWM2OD1|ND64OVM2KM7:TR?= NVz3Xm5KW0GQR1XS
GB-1 NH;QXmhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlPzTWM2OD1|NT6wOFY6KM7:TR?= NFvv[pRUSU6JRWK=
TE-15 NHOyXnFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NU\FTXdUUUN3ME2zOU4zOjN6IN88US=> MWrTRW5ITVJ?
LC4-1 NUTrbFBwT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWL2TG1YUUN3ME2zOU4{QDR5IN88US=> MWXTRW5ITVJ?
NCI-H747 MlrmS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoTETWM2OD1|Nj6xN|Y6KM7:TR?= M2exc3NCVkeHUh?=
NTERA-S-cl-D1 MoTDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIrHUXFKSzVyPUO4Mlc{PDdizszN M2ThcnNCVkeHUh?=
SK-MM-2 Mn[1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVniVYxnUUN3ME20NE4yOTR4IN88US=> MkC1V2FPT0WU
TGW M4PkXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVTJR|UxRTRzLkC1OlMh|ryP NGPl[|lUSU6JRWK=
ONS-76 M{jYW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVHBTmhTUUN3ME20Nk41QDh|IN88US=> MULTRW5ITVJ?
CPC-N MoHLS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFSzN|BKSzVyPUSyMlk6PzFizszN MnXYV2FPT0WU
ES4 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUHJR|UxRTR2LkSxOVMh|ryP NFPwWY5USU6JRWK=
Daudi NI[3TGRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXrJR|UxRTR3LkC4Nlch|ryP NH31XJhUSU6JRWK=
MOLT-4 NVXvWGc{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXPDfllkUUN3ME20OU4xQDV|IN88US=> M3TRR3NCVkeHUh?=
HT-144 NFfNWJJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1XJemlEPTB;NE[uO|I3KM7:TR?= MlO0V2FPT0WU
SW872 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlrYTWM2OD12OD6xPVM{KM7:TR?= NVvIflFLW0GQR1XS
D-283MED MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmfxTWM2OD12OD6zOVQzKM7:TR?= M3\m[3NCVkeHUh?=
NCI-H2126 NXKwUGd7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXPJR|UxRTR6Lki0O|Yh|ryP NUH4T3VCW0GQR1XS
NCI-SNU-16 M4PDSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUn4XZBjUUN3ME20PU4zOTR|IN88US=> M3Xl[HNCVkeHUh?=
CESS M1W3fGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M33EW2lEPTB;NEmuOVA5QCEQvF2= NGPIeWdUSU6JRWK=
A101D MkLZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1G4OWlEPTB;NEmuPVc{PiEQvF2= NX3G[oFtW0GQR1XS

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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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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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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 (64)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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