Dovitinib (TKI-258)

Catalog No.S1018 Synonyms: CHIR-258

For research use only.

Dovitinib (TKI258, CHIR258) is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM, also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less potent to InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R and HER2 in cell-free assays. Phase 4.

Dovitinib (TKI-258) Chemical Structure

CAS No. 405169-16-6

Selleck's Dovitinib (TKI-258) has been cited by 40 publications

Purity & Quality Control

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Biological Activity

Description Dovitinib (TKI258, CHIR258) is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM, also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less potent to InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R and HER2 in cell-free assays. Phase 4.
Targets
FLT3 [1]
(Cell-free assay)
c-Kit [1]
(Cell-free assay)
FGFR1 [1]
(Cell-free assay)
VEGFR3/FLT4 [1]
(Cell-free assay)
FGFR3 [1]
(Cell-free assay)
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1 nM 2 nM 8 nM 8 nM 9 nM
In vitro

Dovitinib potently inhibits the FGF-stimulated growth of WT and F384L-FGFR3-expressing B9 cells with IC50 of 25 nM. In addition, Dovitinib inhibits proliferation of B9 cells expressing each of the various activated mutants of FGFR3. Interestingly, there are minimal observed differences in the sensitivity of the different FGFR3 mutations to Dovitinib, with the IC50 ranging from 70 to 90 nM for each of the various mutations. IL-6-dependent B9 cells containing vector only (B9-MINV cells are resistant to the inhibitory activity of Dovitinib at concentrations up to 1 μM. Dovitinib inhibits cell proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 of 90 nM (KMS11 and OPM2) and 550 nM, respectively. Dovitinib inhibits FGF-mediated ERK1/2 phosphorylation and induces cytotoxicity in FGFR3-expressing primary MM cells. BMSCs does confer a modest degree of resistance with 44.6% growth inhibition for cells treated with 500 nM Dovitinib and cultured on stroma compared with 71.6% growth inhibition for cells grown without BMSCs. Dovitinib inhibits proliferation of M-NFS-60, an M-CSF growth-driven mouse myeloblastic cell line with a median effective concentration (EC50) of 220 nM. [1] Treatment of SK-HEP1 cells with Dovitinib results in a dose-dependent reduction in cell number and G2/M phase arrest with reduction in the G0/G1 and S phases, inhibition of anchorage-independent growth and blockage of bFGF-induced cell motility. The IC50 for Dovitinib in SK-HEP1 cells is approximately 1.7 μM. Dovitinib also significantly reduces the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α) and ERK1/2 but not Akt in both SK-HEP1 and 21-0208 cells. In 21-0208 HCC cells, Dovitinib significantly inhibits bFGF-induced phosphorylation of FGFR-1, FRS2-α, ERK1/2 but not Akt. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SupB15 M2XJOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVTteYFPUUN3ME2wMlQ1QSEQvF2= Mn3WQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{MEKwO|MoRjJ3MkCyNFc{RC:jPh?=
SupB15-R MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2PHU2lEPTB;MD61OVgh|ryP NEXLb|c9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUKwNlA4Oyd-MkWyNFIxPzN:L3G+
BaF3-pSRα NYKzbXhzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3zhUGlEPTB;MD62Olgh|ryP NWiwSYlnRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWyNFIxPzNpPkK1NlAzODd|PD;hQi=>
BaF3-p210Bcr-Abl M1H0[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV;NflBRUUN3ME2wMlY6OiEQvF2= NYn5c2tvRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWyNFIxPzNpPkK1NlAzODd|PD;hQi=>
BaF3-p210Bcr-Abl-T315I NF;kcpBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3n3[2lEPTB;Mj62NlYh|ryP NUm4ZpBkRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWyNFIxPzNpPkK1NlAzODd|PD;hQi=>
CCRF-CEM NFz0T|NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MWfJR|UxRTBwM{m4JO69VQ>? M3fZ[|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3MkCyNFczLz5{NUKwNlA4OjxxYU6=
CEM/C2 MorYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NInIe|ZKSzVyPUGuNVI2KM7:TR?= MnT1QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{MEKwO|IoRjJ3MkCyNFczRC:jPh?=
Nalm-6 NELzelVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3;MTmlEPTB;MD6zPFIh|ryP NX\T[JNKRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWyNFIxPzJpPkK1NlAzODd{PD;hQi=>
SEM-K2 MlXSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MUfJR|UxRTBwMEKyJO69VQ>? MmXuQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{MEKwO|IoRjJ3MkCyNFczRC:jPh?=
HB-1119 NVrtNFVpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX3zdmJXUUN3ME2wMlAzQCEQvF2= M2Tu[|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3MkCyNFczLz5{NUKwNlA4OjxxYU6=
RS4:11 NFP1UmZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEm2[5ZKSzVyPUKuPFEh|ryP MoqzQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{MEKwO|IoRjJ3MkCyNFczRC:jPh?=
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SEM-K2 NEjnT|NCeG:ydH;zbZMhSXO|YYm= MnzPNE4yNzFizszN MYGyOEBp NVvndItNcW6mdXPld{Bm[XKueTDhdI9xfG:|aYOgc4YhW0WPLVuyJINmdGy|IHH0JFAvOSEQvF2gZYZ1\XJiMkSgbC=> NULofW5LRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWyNFIxPzJpPkK1NlAzODd{PD;hQi=>
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HT-29 MljCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnnDTWM2OD13LkKxMlk{KM7:TR?= M3jWeVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2NEm1O|UxLz5{NES5OVc2ODxxYU6=
SW-480 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUjJR|UxRTRwM{OwMlQ4KM7:TR?= MV:8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDR7NUe1NEc,OjR2OUW3OVA9N2F-
CaCO2 MoHNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWDJR|UxRTNwMkOwMlY1KM7:TR?= NF:5e|c9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NES5OVc2OCd-MkS0PVU4PTB:L3G+
LS174T NIPSOGtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYDJR|UxRTRwM{OwMlQ4KM7:TR?= NHfsRZk9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NES5OVc2OCd-MkS0PVU4PTB:L3G+
HEC-1A MnrOSpVv[3Srb36gRZN{[Xl? NXfHdoN[OC5yNT:wMlEwOC53IN88US=> NGL1cng4OiCq NFHkWlVk[XW|ZYOgZUBl\WO{ZXHz[UBqdiCVVFHUN{whTVKNLDDhcoQhSUuWIIDoc5NxcG:{eXzheIlwdg>? MUO8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDR7NUe1NEc,OjR2OUW3OVA9N2F-
AN3CA NWO3TmRzTnWwY4Tpc44hSXO|YYm= MVqwMlA2NzBwMT:wMlUh|ryP NYnmelZOPzJiaB?= MnOxZ4F2e2W|IHGg[IVkemWjc3WgbY4hW1SDVEOsJGVTUyxiYX7kJGFMXCCyaH;zdIhwenmuYYTpc44> MlrnQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR2OUW3OVAoRjJ2NEm1O|UxRC:jPh?=
MFE-296  NH;zSXBHfW6ldHnvckBCe3OjeR?= NVq2W2VuOC5yNT:wMlEwOC53IN88US=> NIr3NmE4OiCq MXrjZZV{\XNiYTDk[YNz\WG|ZTDpckBUXEGWMzygSXJMNCCjbnSgRWtVKHCqb4PwbI9zgWyjdHnvci=> MljkQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR2OUW3OVAoRjJ2NEm1O|UxRC:jPh?=
UMC3 NIrVeXVE\WyuIG\pZYJqdGm2eTDBd5NigQ>? M{XzdVEuOTBizszN NEfIUok4OiCq NEfQdWlqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2ViZHXw[Y5l\W62IH3hco5meg>? MXq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDN{NUS2NUc,OjR|MkW0OlE9N2F-
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HU456 M3fy[2NmdGxiVnnhZoltcXS7IFHzd4F6 MX[xMVExKM7:TR?= Mm\6O|IhcA>? MlnQbY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> Mkf4QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR|MkW0OlEoRjJ2M{K1OFYyRC:jPh?=
MGHU4 M12x[2NmdGxiVnnhZoltcXS7IFHzd4F6 MmT4NU0yOCEQvF2= NEPuSnY4OiCq M3\aTIlvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\SCmZYDlcoRmdnRibXHucoVz NXfQ[WEzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkSzNlU1PjFpPkK0N|I2PDZzPD;hQi=>
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RT112 NUH1SGVtS2WubDDWbYFjcWyrdImgRZN{[Xl? MY[xMVExKM7:TR?= NV\3WXlPPzJiaB?= NVX4NHBzcW6qaXLpeJMh[2WubDDndo94fGhiaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? NVrIcXVIRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkSzNlU1PjFpPkK0N|I2PDZzPD;hQi=>
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BFTC905 NV3zN4dqS2WubDDWbYFjcWyrdImgRZN{[Xl? MXSxMVExKM7:TR?= Moe3O|IhcA>? M4LNPYlvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\SCmZYDlcoRmdnRibXHucoVz M3;xXVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2M{K1OFYyLz5{NEOyOVQ3OTxxYU6=
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C666-1 NH33bZhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NImwNG8xNjFvMUCg{txO NHrmZXE1QMLiaB?= MmrobY5lfWOnczDHNk9OKGSnbHH5JIlvKGFiY3;uZ4VvfHKjdHnvck1l\XCnbnTlcpQhdWGwbnXy NUfG[HdORGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkSyN|gxQTRpPkK0NlM5ODl2PD;hQi=>
HeLa MoTKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlP3NE4yNTFyIN88US=> MWWyOEBp NVXUPHNwcW6mdXPld{BIOi:PIHHydoV{fCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? MYW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDJ|OEC5OEc,OjR{M{iwPVQ9N2F-
Hep3B NX:2UJJOT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlWzNE4yNTFyIN88US=> NX\5OIk{OjRiaB?= NVrCXm5qcW6mdXPld{BIOsLiYYLy[ZN1yqB? MlLNQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR{M{iwPVQoRjJ2MkO4NFk1RC:jPh?=
HepG2 M4nTcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWS1[nNrPDhiaB?= NF3LRpVKSzVyPUKuO|I4KMLzIECuOFI6KM7:TR?= MnHPQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN3NE[1PVEoRjJ|NUS2OVkyRC:jPh?=
Hep3B MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHz6Z4Q1QCCq NH\FN29KSzVyPUSuNlI{KMLzIECuPFM6KM7:TR?= MYe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzV2NkW5NUc,OjN3NE[1PVE9N2F-
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Huh7 M2W3emdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkDFOFghcA>? M4\VWGlEPTB;MUWuNFA4KMLzIEeuN|M1KM7:TR?= MVe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzV2NkW5NUc,OjN3NE[1PVE9N2F-
HepG2 MnHOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFnQWmQ4OiCq NGrnRm5KSzVyPUGuNlAxKMLzIECuNlI3KM7:TR?= M2n0NlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NUS2OVkyLz5{M{W0OlU6OTxxYU6=
Hep3B NHu0NFBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHS5Zlg4OiCq NHXQTZNKSzVyPUCuPFkzKMLzIECuNFQ1KM7:TR?= M{DJRVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NUS2OVkyLz5{M{W0OlU6OTxxYU6=
PLC/PRF5 NIj4W4ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWKxN5JTPzJiaB?= MnPXTWM2OD1|LkGxNEDDuSByLkOzO{DPxE1? NW\1bYV1RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO1OFY2QTFpPkKzOVQ3PTlzPD;hQi=>
Huh7 Mm\JS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX61V|dOPzJiaB?= MW\JR|UxRTNwOUiwJOKyKDBwOECzJO69VQ>? NVvnWIEzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO1OFY2QTFpPkKzOVQ3PTlzPD;hQi=>
MFE280 M3HSb2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1jIN2lEPTB;MD60NkDDuSByLkC2JO69VQ>? NYPJc5g1RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO0OFM5ODVpPkKzOFQ{QDB3PD;hQi=>
AN3CA Ml\YS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWnJR|UxRTBwNUCgxtEhOC5zMDFOwG0> NFr4O5I9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{S0N|gxPSd-MkO0OFM5ODV:L3G+
HEC155 M362ZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFXZPZhKSzVyPUCuOlYhyrFiMD6wPUDPxE1? MmrEQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN2NEO4NFUoRjJ|NESzPFA2RC:jPh?=
MFE296 NYPH[o5ET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYLJR|UxRTBwNk[gxtEhOC5zOTFOwG0> Ml3FQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN2NEO4NFUoRjJ|NESzPFA2RC:jPh?=
SPAC1S M4PB[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVzJR|UxRTBwN{egxtEhOC5yODFOwG0> MWq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzR2M{iwOUc,OjN2NEO4NFU9N2F-
RL952 M{jyUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWrJdGM5UUN3ME2wMlk{KMLzIECuNFEh|ryP NIjZS5c9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{S0N|gxPSd-MkO0OFM5ODV:L3G+
EN1 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4PYNmlEPTB;MT6wNkDDuSByLkK1JO69VQ>? NX\kd5U{RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO0OFM5ODVpPkKzOFQ{QDB3PD;hQi=>
SNGII M{X5SWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MojITWM2OD1zLkK0JOKyKDBwMkig{txO M3f2VVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NESzPFA2Lz5{M{S0N|gxPTxxYU6=
ISHIKAWA Mn:4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3nRUmlEPTB;MT6zNEDDuSByLkGxJO69VQ>? MUm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzR2M{iwOUc,OjN2NEO4NFU9N2F-
HEC1A MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYPJR|UxRTFwM{SgxtEhOC5|MDFOwG0> MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzR2M{iwOUc,OjN2NEO4NFU9N2F-
KLE MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NI\kU3dKSzVyPUGuN|chyrFiMD6wNkDPxE1? NVvYS5Y5RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO0OFM5ODVpPkKzOFQ{QDB3PD;hQi=>
SNGM NGToOVZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFvZ[odKSzVyPUGuOFIhyrFiMD6xN{DPxE1? MXW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzR2M{iwOUc,OjN2NEO4NFU9N2F-
USPC2 MWfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIjuUJJKSzVyPUGuOlIhyrFiMD6wNUDPxE1? NIHLNWI9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{S0N|gxPSd-MkO0OFM5ODV:L3G+
EN MlzCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYrKPFRzUUN3ME2xMlY3KMLzIECuNFEh|ryP NH74XFE9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{S0N|gxPSd-MkO0OFM5ODV:L3G+
MFE319 NYT6NnFlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUnJR|UxRTFwOEegxtEhOC52NTFOwG0> NX71[5M4RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO0OFM5ODVpPkKzOFQ{QDB3PD;hQi=>
EFE184 M{Dwemdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MULJR|UxRTJwMESgxtEhOC5zMzFOwG0> M4SxWlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NESzPFA2Lz5{M{S0N|gxPTxxYU6=
ECC1 MkTIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4fCb2lEPTB;Mj6wO{DDuSByLkCxJO69VQ>? M3j2bFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NESzPFA2Lz5{M{S0N|gxPTxxYU6=
HEC1B Ml3xS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1u0UmlEPTB;Mj61O{DDuSByLkKzJO69VQ>? MnvPQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN2NEO4NFUoRjJ|NESzPFA2RC:jPh?=
USPC1 MkPhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmnsTWM2OD1{Lk[wJOKyKDBwMUOg{txO M1W2bFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ|NESzPFA2Lz5{M{S0N|gxPTxxYU6=
SPAC1L NHjld45Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXH0fXN2UUN3ME2zMlA3KMLzIEGuNVQh|ryP MXi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzR2M{iwOUc,OjN2NEO4NFU9N2F-
HUVEC M1e5fmNmdGxiVnnhZoltcXS7IFHzd4F6 MUGwMVI2KM7:TR?= NV;ofnR6PzJiaB?= M3HOeGROW09? MUnpcohq[mm2czDj[YxtKGe{b4f0bEBqdiCjIHTvd4Uh\GWyZX7k[Y51KG2jbn7ldi=> NFPZ[nc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{KyPFAyPyd-MkOyNlgxOTd:L3G+
HMVEC MnjjR4VtdCCYaXHibYxqfHliQYPzZZk> NXOwW2tzOC1{NTFOwG0> MkjDO|IhcA>? Mom1SG1UVw>? NXTWd2w3cW6qaXLpeJMh[2WubDDndo94fGhiaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? NXn5ZWZLRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkOyNlgxOTdpPkKzNlI5ODF5PD;hQi=>
MHCC-97H NIf6S4VE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MYewMVI2KM7:TR?= NWTRbHR1PzJiaB?= MkDiSG1UVw>? MnnubY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> MoCyQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN{MkiwNVcoRjJ|MkK4NFE4RC:jPh?=
SMMC7721 NX7wWpVWS2WubDDWbYFjcWyrdImgRZN{[Xl? MYqwMVI2KM7:TR?= NGjVSZE4OiCq MkCySG1UVw>? Ml\3bY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> NH\he|I9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{KyPFAyPyd-MkOyNlgxOTd:L3G+
Huh-7 NG\JVVBCeG:ydH;zbZMhSXO|YYm= NHf0VHYxNTF{LkWg{txO MY[yOEBp M17DWWROW00EoB?= M2[x[pNmdnOrdHn6[ZMhUEOFIHPlcIx{KHSxIGTSRWlNNSCjbnSgeIlo[XS3eoXtZYIucW6mdXPl[EBieG:ydH;zbZMhcW5iYTDkc5NmNWSncHXu[IVvfCCvYX7u[ZI> MWm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOjJ|MES3PUc,OjJ{M{C0O|k9N2F-
Sk-Hep1 M33HVGFxd3C2b4Ppd{BCe3OjeR?= NEfMNGMxNTF{LkWg{txO MV6yOEBp MkXzSG1UV8Li NH7STml{\W6|aYTpfoV{KEiFQzDj[YxteyC2bzDUVmFKVC1iYX7kJJRq\2G2dYr1cYFjNWmwZIXj[YQh[XCxcITvd4l{KGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz MlntQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjJ{M{C0O|koRjJ{MkOwOFc6RC:jPh?=
Hep3B NEfZV4NCeG:ydH;zbZMhSXO|YYm= M4e1XFAuOTJwNTFOwG0> NWm3TGRROjRiaB?= MYTEUXNQyqB? NYnafpZPe2Wwc3n0bZpmeyCKQ1OgZ4VtdHNidH:gWHJCUUxvIHHu[EB1cWejdIX6eY1i[i2rbnT1Z4VlKGGyb4D0c5NqeyCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>? MY[8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOjJ|MES3PUc,OjJ{M{C0O|k9N2F-
PLC5 M1P5cGFxd3C2b4Ppd{BCe3OjeR?= NYXKXYx5OC1zMj61JO69VQ>? NF\2[GEzPCCq MnnvSG1UV8Li NEfEOIh{\W6|aYTpfoV{KEiFQzDj[YxteyC2bzDUVmFKVC1iYX7kJJRq\2G2dYr1cYFjNWmwZIXj[YQh[XCxcITvd4l{KGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz NX;wU2UxRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKyN|A1PzlpPkKyNlMxPDd7PD;hQi=>
PLC5 M13kbWNmdGxiVnnhZoltcXS7IFHzd4F6 NYjuTod2OC1zNTFOwG0> M1ewUlczKGh? M4mz[pJm\HWlZYOgZ4VtdCC4aXHibYxqfHliaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XMEoB?= NWfyRWt1RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKxPFA{ODhpPkKyNVgxOzB6PD;hQi=>
Hep3B M3n1SGNmdGxiVnnhZoltcXS7IFHzd4F6 M{L0ZlAuOTVizszN M1Hle|czKGh? MYfy[YR2[2W|IHPlcIwhfmmjYnnsbZR6KGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVzyqB? NIXLOmc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{MkG4NFMxQCd-MkKxPFA{ODh:L3G+
Sk-Hep1 Mn:3R4VtdCCYaXHibYxqfHliQYPzZZk> M3XNfFAuOTVizszN M4HofFczKGh? M3OxNpJm\HWlZYOgZ4VtdCC4aXHibYxqfHliaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XMEoB?= MUS8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOjF6MEOwPEc,OjJzOECzNFg9N2F-
Huh-7 M{fGZ2NmdGxiVnnhZoltcXS7IFHzd4F6 NVG0W4dpOC1zNTFOwG0> NYD5TYtCPzJiaB?= NEfZW|hz\WS3Y3XzJINmdGxidnnhZoltcXS7IHnuJIEh\G:|ZT3k[ZBmdmSnboSgcYFvdmW{wrC= MnrvQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjJzOECzNFgoRjJ{MUiwN|A5RC:jPh?=
PLC5 NX\6WJVOSXCxcITvd4l{KEG|c3H5 MViwMVE2KM7:TR?= M33HWVI1KGh? MmDkbY5kemWjc3XzJIFxd3C2b4TpZ{Bk\WyuIHTlZZRpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVzyqB? M{K4T|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ{MUiwN|A5Lz5{MkG4NFMxQDxxYU6=
Hep3B MVPBdI9xfG:|aYOgRZN{[Xl? MlvaNE0yPSEQvF2= NHi2PGQzPCCq NETSUVZqdmO{ZXHz[ZMh[XCxcITveIlkKGOnbHyg[IVifGhiaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XMEoB?= NYTQToxTRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKxPFA{ODhpPkKyNVgxOzB6PD;hQi=>
Sk-Hep1 MVnBdI9xfG:|aYOgRZN{[Xl? MY[wMVE2KM7:TR?= MnrJNlQhcA>? M2DrOIlv[3KnYYPld{BieG:ydH;0bYMh[2WubDDk[YF1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5mesLi Mli3QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjJzOECzNFgoRjJ{MUiwN|A5RC:jPh?=
Huh-7 M{TUR2Fxd3C2b4Ppd{BCe3OjeR?= M3X0VVAuOTVizszN MlLKNlQhcA>? MoXqbY5kemWjc3XzJIFxd3C2b4TpZ{Bk\WyuIHTlZZRpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVzyqB? NVe4VWh6RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKxPFA{ODhpPkKyNVgxOzB6PD;hQi=>
PLC5 MlTISpVv[3Srb36gRZN{[Xl? NWHZPVM3OC1zMDFOwG0> NEfPZYszPCCq MYLjZZV{\XNiZH;z[U1l\XCnbnTlcpQhTE6DIH\yZYdu\W62YYTpc44> M1rkWFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ{MUiwN|A5Lz5{MkG4NFMxQDxxYU6=
Hep3B MULGeY5kfGmxbjDBd5NigQ>? MlHVNE0yOCEQvF2= NXXmfo5XOjRiaB?= MVnjZZV{\XNiZH;z[U1l\XCnbnTlcpQhTE6DIH\yZYdu\W62YYTpc44> NYW2Um9SRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKxPFA{ODhpPkKyNVgxOzB6PD;hQi=>
Sk-Hep1 NWDsd|N1TnWwY4Tpc44hSXO|YYm= MmHnNE0yOCEQvF2= MXiyOEBp MnjIZ4F2e2W|IHTvd4Uu\GWyZX7k[Y51KESQQTDmdoFodWWwdHH0bY9v NYnN[HVPRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkKxPFA{ODhpPkKyNVgxOzB6PD;hQi=>
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BT-37 NGjHS2dyUFSVIHHzd4F6 NU\RfldweUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC|Y4Ll[Y4h\m:{IFLUMVM4KGOnbHzz MYq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
NB-EBc1 MljydWhVWyCjc4PhfS=> NY\FWYp7eUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC|Y4Ll[Y4h\m:{IF7CMWVD[zFiY3XscJM> MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
U-2 OS NVnqbWdHeUiWUzDhd5NigQ>? MXnxTHRUKG:oIIDl[IlifHKrYzDjZY5k\XJiY3XscEBtcW6nczD0c{Bq\GWwdHnmfUBufWy2aYDs[UBweHCxcoT1col1cWW|IH\vdkBlenWpIILldJVzeG:|aX7nPkBRemmvYYL5JJNkemWnbjDmc5IhXS1{IF;TJINmdGy| NWjrdHZ{RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N|UyOzlpPkK5OFM2OTN7PD;hQi=>
Saos-2 MV7xTHRUKGG|c3H5 MULxTHRUKG:oIIDl[IlifHKrYzDjZY5k\XJiY3XscEBtcW6nczD0c{Bq\GWwdHnmfUBufWy2aYDs[UBweHCxcoT1col1cWW|IH\vdkBlenWpIILldJVzeG:|aX7nPkBRemmvYYL5JJNkemWnbjDmc5IhW2Gxcz2yJINmdGy| NFLBcXA9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
SK-N-SH Mk\xdWhVWyCjc4PhfS=> MoPOdWhVWyCxZjDw[YRq[XS{aXOgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hcWSnboTp[pkhdXWudHnwcIUhd3Cyb4L0eY5qfGmnczDmc5Ih\HK3ZzDy[ZB2enCxc3nu[|ohWHKrbXHyfUB{[3KnZX6g[o9zKFONLV6tV2gh[2WubIO= MW[8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
NB1643 NELWN5JyUFSVIHHzd4F6 NGDDWpVyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiTlKxOlQ{KGOnbHzz MYS8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
LAN-5 NU[2S244eUiWUzDhd5NigQ>? NUHxRYFEeUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC|Y4Ll[Y4h\m:{IFzBUk02KGOnbHzz MX:8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
BT-12 NGnWb2ZyUFSVIHHzd4F6 MnXUdWhVWyCxZjDw[YRq[XS{aXOgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hcWSnboTp[pkhdXWudHnwcIUhd3Cyb4L0eY5qfGmnczDmc5Ih\HK3ZzDy[ZB2enCxc3nu[|ohWHKrbXHyfUB{[3KnZX6g[o9zKEKWLUGyJINmdGy| M4TDTlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
Rh18 MVzxTHRUKGG|c3H5 NH3nZ5ByUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiUnixPEBk\Wyucx?= MVK8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
OHS-50 NH7OXZJyUFSVIHHzd4F6 NHLsfXVyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiT1jTMVUxKGOnbHzz MmPPQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN|koRjJ7NEO1NVM6RC:jPh?=
RD M3vDNZFJXFNiYYPzZZk> NEPIWlVyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiUlSgZ4VtdHN? NFz2dmU9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
insect cells MoTqSpVv[3Srb36gZZN{[Xl? Mk\LNUB1dyB2IHjydy=> NHvkTmxKdmirYnn0bY9vKG:oIILlZ49u[mmwYX70JGZITlJzIDj1cotvd3ewIH;ybYdqdiliZYjwdoV{e2WmIHnuJIJi[3Wub4\pdpV{KGmwZnXjeIVlKGmwc3XjeEBk\WyuczD1d4lv\yCJR1fHVWRIU0S\SW\MVGkh[XNic4Xid5Rz[XSnIHHmeIVzKDFidH:gOEBpenNiYomgeIlu\S2{ZYPvcJZm\CCobIXvdoV{[2WwY3WgZZN{[XluIFnDOVA:OC5yMElOwG0> Mk\oQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB3MEO5N|goRjNyNUCzPVM5RC:jPh?=
NCI-H1703 NYL5d2hNTnWwY4Tpc44h[XO|YYm= MoO1NVAhfU1? Mlv5NlQhcHK| MortTY5pcWKrdHnvckBw\iCWTlnLJIlvKGi3bXHuJG5EUS2KMUewN{Bk\WyuczD0doFve2[nY4Tl[EB4cXSqIHzlcpRqfmm{YXygeoVkfG:{IEfUSnAh[XO|ZYPz[YQh[XNicnXkeYN1cW:wIH;mJGdUUzNiaX7obYJqfG:{IGigZYN1cX[jdHXkJHRPUUtvbXXkbYF1\WRiV370M3RETi:kZYThMYNifGWwaX6t[IVx\W6mZX70JJRz[W6|Y4LpdJRqd25iYYSgNVAhfU1iYX\0[ZIhOjRiaILzJIJ6KGy3Y3nm[ZJie2VicnXwc5J1\XJiYYPzZZk> MUC8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQly1NlI5QTJxJ{7DbGVOSkx:L3G+
LoVo NYHJR2JoS3m2b4TvfIlkcXS7IHHzd4F6 M{PJOlExKHWP MVO3NkBpenN? Mnn3R5l1d3SxeHnjbZR6KGGpYXnud5QhX262L3LleIEu[2G2ZX7pckB{cWewYXzsbY5oKGSncHXu[IVvfCCqdX3hckBNd1[xIHPlcIx{KGG|c3Xzd4VlKGG|IHPlcIwhfmmjYnnsbZR6KGG2IEGwJJVOKGGodHXyJFczKGi{czDifUBCXFCuaYTlJIF{e2G7 NEnxNlA9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmw2OjJ6OUKvK|5EcEWPQly8M4E,
HCT116 NVTtSXg{S3m2b4TvfIlkcXS7IHHzd4F6 MmfNNVAhfU1? MX23NkBpenN? MnPuR5l1d3SxeHnjbZR6KGGpYXnud5QhX262L3LleIEu[2G2ZX7pckB{cWewYXzsbY5oKGSncHXu[IVvfCCqdX3hckBJS1RzMU[gZ4VtdHNiYYPz[ZN{\WRiYYOgZ4VtdCC4aXHibYxqfHliYYSgNVAhfU1iYX\0[ZIhPzJiaILzJIJ6KEGWUHzpeIUh[XO|YYm= MVO8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQly1NlI5QTJxJ{7DbGVOSkx:L3G+
Assay
Methods Test Index PMID
Western blot CDK1 / p-CDK1 / p53 / p21 ; p-PDGFR-β / PDGFR-β / p-ERK / ERK ; p-VEGFR-2 / VEGFR-2 / p-FGFR-1 / FGFR-1 ; p-STAT3 / STAT3 / Mcl-1 / LC3 / Beclin 1 / p62 24238094 23228017 31485222
Growth inhibition assay Cell viability 28467797
In vivo Dovitinib induces both cytostatic and cytotoxic responses in vivo resulting in regression of FGFR3-expressing tumors.[1] Dovitinib shows a dose- and exposure-dependent inhibition of target receptor tyrosine kinases (RTKs) expressed in tumor xenografts. Dovitinib potently inhibits tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFRβ/VEGFR2 signaling pathways. In an orthotopic model, Dovitinib potently inhibits primary tumor growth and lung metastasis and significantly prolonged mouse survival. [2] Administration of Dovitinib results in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm3). [3]

Protocol (from reference)

Kinase Assay:[1]
  • In vitro kinase assays:

    The inhibitory concentration of 50% (IC50) values for the inhibition of RTKs by Dovitinib are determined in a time-resolved fluorescence (TRF) or radioactive format, measuring the inhibition by Dovitinib of phosphate transfer to a substrate by the respective enzyme. The kinase domains of FGFR3, FGFR1, PDGFRβ, and VEGFR1-3 are assayed in 50 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), pH 7.0, 2 mM MgCl2, 10 mM MnCl2 1 mM NaF, 1 mM dithiothreitol (DTT), 1 mg/mL bovine serum albumin (BSA), 0.25 μM biotinylated peptide substrate (GGGGQDGKDYIVLPI), and 1 to 30 μM adenosine triphosphate (ATP) depending on the Km for the respective enzyme. ATP concentrations are at or just below Km. For c-KIT and FLT3 reactions the pH is raised to 7.5 with 0.2 to 8 μM ATP in the presence of 0.25 to 1 μM biotinylated peptide substrate (GGLFDDPSYVNVQNL). Reactions are incubated at room temperature for 1 to 4 hours and the phosphorylated peptide captured on streptavidin-coated microtiter plates containing stop reaction buffer (25 mM EDTA [ethylenediaminetetraacetic acid], 50 mM HEPES, pH 7.5). Phosphorylated peptide is measured with the DELFIA TRF system using a Europium-labeled antiphosphotyrosine antibody PT66. The concentration of Dovitinib for IC50 is calculated using nonlinear regression with XL-Fit data analysis software version 4.1 (IDBS). Inhibition of colony-stimulating factor-1 receptor (CSF-1R), PDGFRα, insulin receptor (InsR), and insulin-like growth factor receptor 1 (IGFR1) kinase activity is determined at ATP concentrations close the Km for ATP.

Cell Research:[1]
  • Cell lines: B9 cells, MM cell lines
  • Concentrations: 100 nM
  • Incubation Time: 48-96 hours
  • Method: Cell viability is assessed by 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) dye absorbance. Cells are seeded in 96-well plates at a density of 5 × 103 (B9 cells) or 2 × 104 (MM cell lines) cells per well. Cells are incubated with 30 ng/mL aFGF and 100 μg/mL heparin or 1% IL-6 where indicated and increasing concentrations of Dovitinib. For each concentration of Dovitinib, 10 μL aliquots of drug or DMSO diluted in culture medium is added. For drug combination studies, cells are incubated with 0.5 μM dexamethasone, 100 nM Dovitinib, or both simultaneously where indicated. To evaluate the effect of Dovitinib on growth of MM cells adherent to BMSCs, 104 KMS11 cells are cultured on BMSC-coated 96-well plates in the presence or absence of Dovitinib. Plates are incubated for 48 to 96 hours. For assessment of macrophage colony-stimulating factor (M-CSF)-mediated growth, 5 × 103 M-NFS-60 cells/well are incubated with serial dilutions of Dovitinib with 10 ng/mL M-CSF and without granulocyte-macrophage colony-stimulating factor (GM-CSF). After 72 hours cell viability is determined using Cell Titer-Glo Assay. Each experimental condition is performed in triplicate.
  • (Only for Reference)
Animal Research:[1]
  • Animal Models: 8-week-old female BNX mice bearing KMS11 cells
  • Dosages: 10, 30, or 60 mg/kg
  • Administration: Gavage
  • (Only for Reference)

Solubility (25°C)

In vitro

DMSO 30 mg/mL
(76.44 mM)
Water Insoluble
Ethanol Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing.

30 mg/mL

* 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 392.43
Formula

C21H21FN6O

CAS No. 405169-16-6
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(C5=C(C=CC=C5F)NC4=O)N

In vivo Formulation Calculator (Clear solution)

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

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

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

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02268435 Withdrawn Drug: dovitinib plus imatinib Gastrointestinal Stromal Tumors Asan Medical Center March 2015 Phase 1
NCT01700270 Completed Drug: dovitinib (TKI258)|Drug: fluvoxamine Advanced Solid Tumors Excluding Breast Cancer Novartis Pharmaceuticals|Novartis May 2013 Phase 1
NCT01680796 Withdrawn Drug: Dovitinib|Drug: Bortezomib|Drug: Dexamethasone Multiple Myeloma University of Florida|Novartis Pharmaceuticals February 2013 Phase 1
NCT01266070 Terminated Drug: Dovitinib Von Hippel-Lindau Syndrome M.D. Anderson Cancer Center|Novartis November 2012 Phase 2
NCT01515969 Terminated Drug: Erlotinib hydrochloride|Drug: Dovitinib lactate Non-small Cell Lung Cancer (NSCLC) Recurrent|Non-small Cell Lung Cancer (NSCLC) Stage IV Heather Wakelee|Genentech Inc.|Novartis|Stanford University July 2012 Phase 1

(data from https://clinicaltrials.gov, updated on 2021-09-06)

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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