Regorafenib (BAY 73-4506)

Name: Regorafenib (BAY 73-4506)
Brand: Selleck Chemicals
SKU: S1178
Rating: 5 (133 reviews)

For research use only.

Catalog No.S1178 Synonyms: Fluoro-Sorafenib, Resihance, Stivarga

133 publications

Regorafenib (BAY 73-4506) Chemical Structure

CAS No. 755037-03-7

Regorafenib (BAY 73-4506, Fluoro-Sorafenib, Resihance, Stivarga) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit (c-Kit), RET (c-RET) and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM in cell-free assays, respectively. Regorafenib induces autophagy.

Selleck's Regorafenib (BAY 73-4506) has been cited by 133 publications

Cancer Cell, 2019, 36(2):179-193

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Cell, 2019, 36(2):179-193

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Gastroenterology, 2017, 153(4):1082-1095

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Neoplasia, 2021, 23(3):304-325

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Int J Mol Sci, 2021, 22(3)1502

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Food Funct, 2021, 10.1039/d0fo02270e

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Cancer Res, 2020, 80(21):4815-4827

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Cancers (Basel), 2020, 12(12)E3816

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Front Oncol, 2020, 10:878

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Front Oncol, 2020, 10:563249

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Antiviral Res, 2020, 178:104790

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Arthritis Res Ther, 2020, 22(1):160

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Int J Mol Sci, 2020, 18;21(8):2825

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Cancer Cell Int, 2020, 19;20:58

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Hum Cell, 2020, 10.1007/s13577-020-00420-z

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Hum Cell, 2020, 10.1007/s13577-020-00425-8

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Front Oncol, 2020, 10:694

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Int J Radiat Biol, 2020, 2:1-12

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Front Oncol, 2020, 10:291

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Biochem Biophys Res Commun, 2020, 529(3):699-706

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Onco Targets Ther, 2020, 13:7213-7227

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Nat Cell Biol, 2019, 21(2):203-213

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Gut, 2019, 10.1136/gutjnl-2019-318506

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Cell Rep, 2019, 29(3):573-588

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Br J Pharmacol, 2019, 176(6):787-800

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EBioMedicine, 2019, 41:175-184

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J Med Chem, 2019, 10.1021/acs.jmedchem.9b00855

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Cancers (Basel), 2019, 11(4)

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Cell Death Dis, 2019, 10(10):784

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Cell Death Dis, 2019, 10(9):672

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Br J Cancer, 2019, 120(6):612-620

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Cell Chem Biol, 2019, 10.1016/j.chembiol.2019.04.011

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Mol Cancer Ther, 2019, 18(11):2146-2157

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Cell Commun Signal, 2019, 17(1):85

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Sci Rep, 2019, 9(1):636

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Sci Rep, 2019, 9(1):7103

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Cell Biosci, 2019, 9:88

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Molecules, 2019, 24(7)

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BMC Microbiol, 2019, 19(1):34

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Dis Markers, 2019, 2019:8964015

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FEBS Open Bio, 2019, 9(2):335-347

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Ann Biomed Eng, 2019, 10.1007/s10439-019-02269-2

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Nat Metab, 2019, 1(10):985-995

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Animal Model Exp Med, 2019, 2(4):259-268

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Ann Surg Oncol, 2019, 26(1):139-147

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Mol Cancer Ther, 2018, 17(12):2610-2621

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Endocr Relat Cancer, 2018, 25(4):471-480

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Cancer Sci, 2018, 109(11):3591-3601

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Biochem Biophys Res Commun, 2018, 504(4):878-884

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Anticancer Res, 2018, 38(4):1967-1977

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Chem Sci, 2018, 9(10):2674-2689

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Oncotarget, 2018, 9(56):30869-30882

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BMC Res Notes, 2018, 11(1):859

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Sci Transl Med, 2017, 14;9(394):eaah6144

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Cancer Res, 2017, 77(9):2512-2521

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Arch Toxicol, 2017, 91(8):2921-2938

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Mol Biol Cell, 2017, 28(7):907-921

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Toxicol Sci, 2017, 158(1):213-226

PubMed: 28453775 ( click the link to review the publication )

Sci Rep, 2017, 7(1):1502

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Molecules, 2017, 22(12)

PubMed: 29206199 ( click the link to review the publication )

PLoS One, 2017, 12(3):e0174151

PubMed: 28301591 ( click the link to review the publication )

Curr Cancer Drug Targets, 2017, 17(4):386-401

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Naunyn Schmiedebergs Arch Pharmacol, 2017, 390(11):1125-1134

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Med Sci Monit, 2017, 23:1963-1972

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J Mol Graph Model, 2017,

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Exp Ther Med, 2017, 14(2):1357-1366

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Oncotarget, 2017, 8(4):6102-6113

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Oncotarget, 2017, 8(61):104090-104103

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Oncotarget, 2017, 8(61):103465-103476

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Oncotarget, 2017, 8(69):113444-113459

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Oncotarget, 2017, 8(4):6102-6113

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Oncotarget, 2017, 8(47):83052-83062

PubMed: 29137323 ( click the link to review the publication )
Oncotarget, 2017, 9(3):3605-3618

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Oncotarget, 2017, 8(52):90262-90277

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Oncotarget, 2017, 8(59):99451-99469

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Oncotarget, 2017, 8(1):1449-1468

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Oncotarget, 2017, 9(17):13154-13166

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Oncotarget, 2017, 8(50):87209-87220

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Oncotarget, 2017, 8(12):18832-18847

PubMed: 27902968 ( click the link to review the publication )

Oncotarget, 2017, 8(10):16367-16386

PubMed: 28146421 ( click the link to review the publication )

Oncotarget, 2017, 8(69):113444-113459

PubMed: 29371921 ( click the link to review the publication )

ACS Nano, 2016, 10(11):9999-10012

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Cancer Res, 2016, 76(1):117-26

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Oncogene, 2016, 10.1038/onc.2016.247

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PLoS Genet, 2016, 12(9):e1006279

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Bioinformatics, 2016, 32(12):i253-i261

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ACS Chem Biol, 2016, 11(12):3400-3411

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J Cell Physiol, 2016, 231(5):1097-105

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Sci Rep, 2016, 6:35308

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J Cell Physiol, 2016, 231(10):2286-302

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Oncotarget, 2016, 7(18):26580-92

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Oncotarget, 2016, 7(11):12975-96

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Oncotarget, 2016, 7(14):17290-300

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Oncotarget, 2016, 7(30):47954-47965

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Oncotarget, 2016, 7(26):40398-40417

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EMBO Mol Med, 2015, 7(10):1350-65

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Proc Natl Acad Sci USA, 2015, 112(6):1839-44

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Int J Cancer, 2015, 136(6):1434-44

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J Exp Clin Cancer Res, 2015, 34:90

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J Cell Physiol, 2015, 230(1):131-9

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J Cell Physiol, 2015, 230(10):2552-78

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J Cell Physiol, 2015, 10.1002/jcp.24961

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Drug Metab Dispos, 2015, 43(12):1934-7

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Cancer Biol Ther, 2015, 16(11):1660-70

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Toxicology, 2015, 327:10-21

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J Med Invest, 2015, 62(3-4):195-8

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Oncotarget, 2015,

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Gastroenterology, 2015, 148(7):1438-51

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Oncotarget, 2015, 6(4):1954-66

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Oncotarget, 2015, 6(16):14385-98

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Cell Death Dis, 2014, 5:e1278

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Cancer Cell Int, 2014, 14(1):89

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Cancer Biol Ther, 2014, 15(3):305-16

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Biomed Res Int, 2014, 2014:568693

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Purity & Quality Control

Choose Selective VEGFR Inhibitors

Biological Activity

Description

Targets

RET ^[1] (Cell-free assay)	Raf-1 ^[1] (Cell-free assay)	VEGFR2 ^[1] (Cell-free assay)	Kit ^[1] (Cell-free assay)	VEGFR1 ^[1] (Cell-free assay)	View More
1.5 nM	2.5 nM	4.2 nM	7 nM	13 nM	View More

In vitro

Regorafenib strongly prevents VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with IC50 of 3 nM. In HAoSMCs, regorafenib suppress PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib also inhibits FGFR signaling in MCF-7 breast cancer (BC) cells stimulated with FGF10. Regorafenib very potently inhibited the mutant receptors KIT^K642E and RET^C634W, with IC50 of approximately 20 nM and 10 nM, respectively. Regorafenib inhibits the proliferation of VEGF¹⁶⁵-stimulated HUVECs, with an IC50 of approximately 3 nM. Regorafenib prevents the proliferation of FGF2-stimulated HUVECs and of PDGF-BB-stimulated HAoSMCs with IC50 of 127 nM and 146 nM, respectively. ^[1] Regorafenib targets both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (Raf and p38MAPK). ^[2] Regorafenib suppresses growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. ^[3]

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Formulation	Activity Description	PMID
Hep3B	NIDWOXlCeG:ydH;zbZMhSXO\|YYm=	NID0dY0y6oDVNdMg{txO	NFf6UJE1QCCq		MmLLbY5pcWKrdIOgZ4VtdCCpcn;3eIg>	M4XV[\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4M{K5OlA5Lz5{NkOyPVYxQDxxYU6=
PLC/PRF/5	M2HiVmFxd3C2b4Ppd{BCe3OjeR?=	M{CyVFHjiJN3wrFOwG0>	M{n5WlQ5KGh?		NYfjfYtKcW6qaXLpeJMh[2WubDDndo94fGh?	M{TVN\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4M{K5OlA5Lz5{NkOyPVYxQDxxYU6=
HepG2	NWTvWZNGSXCxcITvd4l{KEG\|c3H5	MUWx5qCUPcLizszN	MVS0PEBp		MlXibY5pcWKrdIOgZ4VtdCCpcn;3eIg>	M4jQdlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4M{K5OlA5Lz5{NkOyPVYxQDxxYU6=
HEK293	M{KzXWZ2dmO2aX;uJGF{e2G7	MXqwMlXjiIoQvF2=	MUiyM\|QwPiCq		MX\y[YR2[2W\|IFfSVFc5KGW6cILld5Nqd25?	NFLUUIk9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUi1PFA{Oid-MkW4OVgxOzJ:L3G+
GEO	MknJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MmHLNE4xOS1{MDFOwG0>	M3zOdlk3KGh?	Ml[xSG1UVw>?	NHTMPINqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?	M2PMd\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
SW48	NFzlcYdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NUjTXpVmOC5yMT2yNEDPxE1?	M1PzT\|k3KGh?	NISxPYhFVVOR	M4XUfYlvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz	M374RlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
HT29	M{\MfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NFjnW20xNjBzLUKwJO69VQ>?	NYDMepRIQTZiaB?=	NHf5VG1FVVOR	NYXkcW1TcW6qaXLpeJMh[2WubDDndo94fGhiaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XJ?	MYq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTh\|OEO5NUc,OjV6M{izPVE9N2F-
SW480	NUTxcGhXT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MUewMlAyNTJyIN88US=>	MYe5OkBp	NU\IUHJnTE2VTx?=	Mn\HbY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmNWSncHXu[IVvfCCvYX7u[ZI>	Mm\JQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV6M{izPVEoRjJ3OEO4N\|kyRC:jPh?=
SW620	MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M1\vVVAvODFvMkCg{txO	M{S3OVk3KGh?	M2TuU2ROW09?	M1Tne4lvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz	NXLiNmVzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkW4N\|g{QTFpPkK1PFM5OzlzPD;hQi=>
HCT116	NV;q[phET3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M4[1VVAvODFvMkCg{txO	NFPO[Y06PiCq	NIrOXXZFVVOR	NWfFTI1CcW6qaXLpeJMh[2WubDDndo94fGhiaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XJ?	MUC8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTh\|OEO5NUc,OjV6M{izPVE9N2F-
LOVO	MlTES5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NHq3bpYxNjBzLUKwJO69VQ>?	NWDjWIZoQTZiaB?=	NGfCc\|NFVVOR	NHiwSXJqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?	M1rGe\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
HCT150	Mo\SS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NWXVNYNROC5yMT2yNEDPxE1?	MWe5OkBp	NV[3fZJxTE2VTx?=	NF72d4lqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?	M1y3V\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
SW48-CR	MmH0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M4fsWFAvODFvMkCg{txO	NF:0UWo6PiCq	Mom5SG1UVw>?	NHmzfFVqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?	M2XlOlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
GEO-CR	MkLOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MXSwMlAyNTJyIN88US=>	MXK5OkBp	M4DZcmROW09?	MlHtbY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmNWSncHXu[IVvfCCvYX7u[ZI>	M3eySVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3OEO4N\|kyLz5{NUizPFM6OTxxYU6=
KB-31	M2q5OWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7				MVTJR\|UxRTVwNdMxNE4{KG6P	MmL5QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV5NUOzOlEoRjJ3N{WzN\|YyRC:jPh?=
KB-G2	MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?				NIGwXnhKSzVyPUmuNeKyOC5zIH7N	Mln0QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV5NUOzOlEoRjJ3N{WzN\|YyRC:jPh?=
LLC-PK1	MnrYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?				MXTJR\|UxRTR{LkFCtVMvOiCwTR?=	NITmdGM9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUe1N\|M3OSd-MkW3OVM{PjF:L3G+
LLC-PK1/MRP2	Mlv3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?				NFLtR4FKSzVyPUiyMlTDuTJwNzDuUS=>	MnLMQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV5NUOzOlEoRjJ3N{WzN\|YyRC:jPh?=
HEK293	Mlf2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?				M2\VNmlEPTB;MUGuNOKyOS5{IH7N	M1;YdlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3N{WzN\|YyLz5{NUe1N\|M3OTxxYU6=
HEK293/OATP1B1	NGnZdJNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=				MmTjTWM2OD14LkNCtVAvOyCwTR?=	MX28ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTd3M{O2NUc,OjV5NUOzOlE9N2F-
HROC18	M13zcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7				MX7JR\|UxRTFwMzFOwG0>	M3PCOFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3M{C5PVE1Lz5{NUOwPVkyPDxxYU6=
HROC24	Mk\YS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?				M3rve2lEPTB;ND62JO69VQ>?	NH\XWGc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUOwPVkyPCd-MkWzNFk6OTR:L3G+
HROC43	MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?				MknoTWM2OD13LkOg{txO	NVjwUZZsRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWzNFk6OTRpPkK1N\|A6QTF2PD;hQi=>
HROC46	NUnKRY5FT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=				NGfj[4lKSzVyPUKuOEDPxE1?	NF3GR4g9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUOwPVkyPCd-MkWzNFk6OTR:L3G+
RJ345	M3XUW2Z2dmO2aX;uJGF{e2G7	MYqwMlUwPSEQvF2=	M3z5UFI1KGh?	MoXjSG1UVw>?	MoO1bY5pcWKrdIOgeIhmKGOnbHygcYloemG2aX;u	M3;xXVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3MkWzPVk1Lz5{NUK1N\|k6PDxxYU6=
RJ348	NIPlW4dHfW6ldHnvckBCe3OjeR?=	MX2wMlUwPSEQvF2=	MXWyOEBp	MULEUXNQ	M37Ob4lvcGmkaYTzJJRp\SClZXzsJI1q\3KjdHnvci=>	MoPLQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{NUO5PVQoRjJ3MkWzPVk1RC:jPh?=
MCF-7	MUXGeY5kfGmxbjDBd5NigQ>?	MkPpNE42NzVizszN	M1O0OlI1KGh?	M1LXR2ROW09?	NG\CSGtqdmirYnn0d{B1cGViY3XscEBucWe{YYTpc44>	MoTiQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjV{NUO5PVQoRjJ3MkWzPVk1RC:jPh?=
MDA-MB-231	NHX6ZmFHfW6ldHnvckBCe3OjeR?=	MWOwMlUwPSEQvF2=	NYPCSVRuOjRiaB?=	MkWwSG1UVw>?	NGrjUoFqdmirYnn0d{B1cGViY3XscEBucWe{YYTpc44>	MYO8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTJ3M{m5OEc,OjV{NUO5PVQ9N2F-
HT15	M1;HU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NFvocI4yNTJyIN88US=>	Mn3qOFghcA>?		MnvFbY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmNWSncHXu[IVvfCCvYX7u[ZI>	NVvEb4xERGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkWwO\|ExOThpPkK1NFcyODF6PD;hQi=>
DLD1	MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MkXPNU0zOCEQvF2=	MmXyOFghcA>?		M1fmZYlvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz	NG\WVZo9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUC3NVAyQCd-MkWwO\|ExOTh:L3G+
HT-29	MmXDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MlzVNU0zOCEQvF2=	NVLScVVNPDhiaB?=		NHexZYtqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?	NHzNTZU9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUC3NVAyQCd-MkWwO\|ExOTh:L3G+
Hct-116	NHHpe41Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M3PxUlEuOjBizszN	NWLTVoNvPDhiaB?=		M4G1eIlvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz	MYC8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTB5MUCxPEc,OjVyN{GwNVg9N2F-
HT15	MkfmRZBweHSxc3nzJGF{e2G7	MoG4NU0yOCEQvF2=	NU[yd\|ZRPDhiaB?=		M3L6[Ylv\HWlZYOgZ4VtdCCmZXH0bEBqdiCjIHTvd4Uu\GWyZX7k[Y51KG2jbn7ldi=>	NEX5emE9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NUC3NVAyQCd-MkWwO\|ExOTh:L3G+
DLD1	MYfBdI9xfG:\|aYOgRZN{[Xl?	MlrZNU0yOCEQvF2=	MWO0PEBp		MX3pcoR2[2W\|IHPlcIwh\GWjdHigbY4h[SCmb4PlMYRmeGWwZHXueEBu[W6wZYK=	MlTwQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjVyN{GwNVgoRjJ3MEexNFE5RC:jPh?=
HT-29	M4KxR2Fxd3C2b4Ppd{BCe3OjeR?=	MkTDNU0yOCEQvF2=	NYnLTXVRPDhiaB?=		MUjpcoR2[2W\|IHPlcIwh\GWjdHigbY4h[SCmb4PlMYRmeGWwZHXueEBu[W6wZYK=	MXW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPTB5MUCxPEc,OjVyN{GwNVg9N2F-
Hct-116	NX24TYZtSXCxcITvd4l{KEG\|c3H5	MWSxMVExKM7:TR?=	MmT0OFghcA>?		NX7hTItVcW6mdXPld{Bk\WyuIHTlZZRpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz	M3zjZVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ3MEexNFE5Lz5{NUC3NVAyQDxxYU6=
GBM5	NFe5R4xCeG:ydH;zbZMhSXO\|YYm=	M1jHdlAvPeLCk{GuNQKBkc7:TR?=	M4POTlI1KGh?	MX\EUXNQ	NEmycIJqdnSncnHjeJMhf2m2aDDsZZBifGmwaXKgeI8hcW6mdXPlJINmdGxiZHXheIg>	M13UeVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2OUGxNlE2Lz5{NEmxNVIyPTxxYU6=
GBM6	MnrvRZBweHSxc3nzJGF{e2G7	MmLSNE426oDVMT6w5qCK\|ryP	NVyzVItFOjRiaB?=	M3foSWROW09?	NH7Td21qdnSncnHjeJMhf2m2aDDsZZBifGmwaXKgeI8hcW6mdXPlJINmdGxiZHXheIg>	MWi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDlzMUKxOUc,OjR7MUGyNVU9N2F-
GBM12	NGLFfXRCeG:ydH;zbZMhSXO\|YYm=	MlO4NE426oDVMT6w5qCK\|ryP	MYOyOEBp	MWTEUXNQ	MY\pcpRmemGldIOge4l1cCCuYYDheIlvcWJidH:gbY5lfWOnIHPlcIwh\GWjdHi=	MWC8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDlzMUKxOUc,OjR7MUGyNVU9N2F-
GBM14	NIPsVGlCeG:ydH;zbZMhSXO\|YYm=	NYP6epNkOC534pETNU4x6oDLzszN	NHfSdI0zPCCq	M3TmfWROW09?	MUXpcpRmemGldIOge4l1cCCuYYDheIlvcWJidH:gbY5lfWOnIHPlcIwh\GWjdHi=	MkPoQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR7MUGyNVUoRjJ2OUGxNlE2RC:jPh?=
Hep3B	M4j5XGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MXix5qCUOi53wrFOwG0>	MkLCNlQwPDhxN{KgbC=>		MWnpcohq[mm2czDj[YxtKGe{b4f0bC=>	M1vkS\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2OEi1PFkxLz5{NEi4OVg6ODxxYU6=
PLC/PRF/5	Ml;sS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MkPINgKBmzJwNdMg{txO	MnXiNlQwPDhxN{KgbC=>		NIPSXIJqdmirYnn0d{Bk\WyuIHfyc5d1cA>?	MWe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDh6NUi5NEc,OjR6OEW4PVA9N2F-
HepG2	MnnUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NW\5cGI2OeLCk{KuOeKh\|ryP	NFnJeYQzPC92OD:3NkBp		MULpcohq[mm2czDj[YxtKGe{b4f0bC=>	NF3LVoc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NEi4OVg6OCd-MkS4PFU5QTB:L3G+
HCT116	MV;GeY5kfGmxbjDBd5NigQ>?	NW\uZlVqOTBxMkCvOFAh\|ryP	NI\RdoQzPCCq		NUPtV3BPcW6mdXPld{BRXU2DIIDyc5RmcW5iYX7kJI1TVkFiZYjwdoV{e2mxbjDpckBiKGSxc3WtJIFv\CC2aX3lMYRmeGWwZHXueEBu[W6wZYK=	MoPkQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR5NkO2NVEoRjJ2N{[zOlEyRC:jPh?=
Lim2405	M3T3PGZ2dmO2aX;uJGF{e2G7	M4O4V\|QxKM7:TR?=	MXuyOEBp		NYrYbYJqcW6mdXPld{BRXU2DIIDyc5RmcW5iYX7kJINmdGxiYYDvdJRwe2m\|	NFvl[Hc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NEe2N\|YyOSd-MkS3OlM3OTF:L3G+
LoVo	NIW4R\|JHfW6ldHnvckBCe3OjeR?=	NWHwV2xwPDBizszN	NFLBTnIzPCCq		Moe3bY5lfWOnczDQWW1CKHC{b4TlbY4h[W6mIHPlcIwh[XCxcITvd4l{	M4[2SFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2N{[zOlEyLz5{NEe2N\|YyOTxxYU6=
Lim1215	NFHMU\|FHfW6ldHnvckBCe3OjeR?=	NXjCOllLPDBizszN	NHjYUHozPCCq		M1jJR4lv\HWlZYOgVHVOSSCycn;0[YlvKGGwZDDj[YxtKGGyb4D0c5Nqew>?	M1n2d\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2N{[zOlEyLz5{NEe2N\|YyOTxxYU6=
SW48	MmnrSpVv[3Srb36gRZN{[Xl?	M4TGNFQxKM7:TR?=	NGLIc5IzPCCq		NXuw[4lbcW6mdXPld{BRXU2DIIDyc5RmcW5iYX7kJINmdGxiYYDvdJRwe2m\|	NY\3d3JjRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS3OlM3OTFpPkK0O\|Y{PjFzPD;hQi=>
RKO	NHGzV3dHfW6ldHnvckBCe3OjeR?=	Ml7XOFAh\|ryP	NVLzTIpDOjRiaB?=		M{XQ[Ylv\HWlZYOgVHVOSSCycn;0[YlvKGGwZDDj[YxtKGGyb4D0c5Nqew>?	NUL2RZJqRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS3OlM3OTFpPkK0O\|Y{PjFzPD;hQi=>
SW837	M{TjT2Z2dmO2aX;uJGF{e2G7	M2[zT\|QxKM7:TR?=	NUjGS2dvOjRiaB?=		NHLOT3VqdmS3Y3XzJHBWVUFicILveIVqdiCjbnSgZ4VtdCCjcH;weI9{cXN?	MXK8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDd4M{[xNUc,OjR5NkO2NVE9N2F-
SW1463	MVXGeY5kfGmxbjDBd5NigQ>?	MWG0NEDPxE1?	Mlr0NlQhcA>?		NIDofIJqdmS3Y3XzJHBWVUFicILveIVqdiCjbnSgZ4VtdCCjcH;weI9{cXN?	NYm5UnUxRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS3OlM3OTFpPkK0O\|Y{PjFzPD;hQi=>
SW480	MnHUSpVv[3Srb36gRZN{[Xl?	M2LqZVQxKM7:TR?=	MVSyOEBp		MXzpcoR2[2W\|IGDVUWEheHKxdHXpckBidmRiY3XscEBieG:ydH;zbZM>	NFrURXQ9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NEe2N\|YyOSd-MkS3OlM3OTF:L3G+
Vaco432	NHWwSWZHfW6ldHnvckBCe3OjeR?=	NUnmRVBGPDBizszN	M3jxWlI1KGh?		Ml31bY5lfWOnczDQWW1CKHC{b4TlbY4h[W6mIHPlcIwh[XCxcITvd4l{	MWW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDd4M{[xNUc,OjR5NkO2NVE9N2F-
Vaco400	NXHyTVZQTnWwY4Tpc44hSXO\|YYm=	MUm0NEDPxE1?	M{TrVFI1KGh?		M3HOfYlv\HWlZYOgVHVOSSCycn;0[YlvKGGwZDDj[YxtKGGyb4D0c5Nqew>?	NUjmT5pbRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS3OlM3OTFpPkK0O\|Y{PjFzPD;hQi=>
DLD1	NXnaOodiTnWwY4Tpc44hSXO\|YYm=	MkDWOFAh\|ryP	MXKyOEBp		NI\UbGNqdmS3Y3XzJHBWVUFicILveIVqdiCjbnSgZ4VtdCCjcH;weI9{cXN?	NUfxSoRvRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS3OlM3OTFpPkK0O\|Y{PjFzPD;hQi=>
HT29	MnGxSpVv[3Srb36gRZN{[Xl?	MWS0NEDPxE1?	NYHxU2FQOjRiaB?=		M2Drb4lv\HWlZYOgVHVOSSCycn;0[YlvKGGwZDDj[YxtKGGyb4D0c5Nqew>?	NIP4[mc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NEe2N\|YyOSd-MkS3OlM3OTF:L3G+
PLC/PRF/5	NH3jWJBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MU[x5qCUPcL3TR?=	MoW2NlQwPDhxN{KgbC=>		NU\xTGhLcW6qaXLpeJMh[2WubDDndo94fGh?	M{i1eFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ\|MU[5NVQ5Lz5{M{G2PVE1QDxxYU6=
HepG2	MoPmS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MX:x5qCUPcL3TR?=	NFrI[HAzPC92OD:3NkBp		MoD3bY5pcWKrdIOgZ4VtdCCpcn;3eIg>	Mnu5QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjNzNkmxOFgoRjJ\|MU[5NVQ5RC:jPh?=
Hep3B	NWD6c\|FFT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NIC2XIgy6oDVNdM1US=>	MkXNNlQwPDhxN{KgbC=>		Ml;rbY5pcWKrdIOgZ4VtdCCpcn;3eIg>	NXvScFg{RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkOxOlkyPDhpPkKzNVY6OTR6PD;hQi=>
BA/F3	M3KyNWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7		MlrnO\|IhcHK\|		NXXNc5FTUW6qaXLpeIlwdiCxZjDLbZQh\XixbjCxNUBl\WyndHnvckApPTV5IITvJFU2QCC{ZYPp[JVmeylibYX0ZY51KCi3bnvuc5dvKG:{aXfpckkhfHKjboPm[YN1\WRiaX6gcY92e2ViQlGvSlMh[2WubIOgZZN{\XO\|ZXSgZZMhcW6qaXLpeIlwdiCxZjDj[YxtKGe{b4f0bEBqdmO3YnH0[YQh\m:{IEeyJIhzeyCkeTDNWHMh[XO\|YYmsJGdKPTBiPTCwMlAzOSEQvF2u	MnK5QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB{MES0OFEoRjNyMkC0OFQyRC:jPh?=
BA/F3	NW\xdXV7T3Kxd4ToJIlvcGmkaYTpc44h[XO\|YYm=		M{e4TVczKGi{cx?=		NIHPVnZKdmirYnn0bY9vKG:oIGTFUE1nfXOnZDDQSGdHWmKndHGgLJVvc26xd36gc5Jq\2mwKTD0doFve2[nY4Tl[EBqdiCvb4Xz[UBDSS:IMzDj[YxteyCjc4Pld5Nm\CCjczDpcohq[mm2aX;uJI9nKGOnbHyg[5Jwf3SqIHnuZ5Vj[XSnZDDmc5IhPzJiaILzJIJ6KE2WUzDhd5NigSxiR1m1NEA:KDBwMEK5JO69VS5?	NYXaVXQ2RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
BA/F3	MoLpS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl?		MVu3NkBpenN?		NVP1bolVUW6qaXLpeIlwdiCxZjDLbZQh\XixbjCxNUBl\WyndHnvckApPTV5IITvJFU2QCC{ZYPp[JVmeyliYX7kJGQ5OT[KIH31eIFvfCCjbnSgWFY4OElibYX0ZY51KCi3bnvuc5dvKG:{aXfpckkhfHKjboPm[YN1\WRiaX6gcY92e2ViQlGvSlMh[2WubIOgZZN{\XO\|ZXSgZZMhcW6qaXLpeIlwdiCxZjDj[YxtKGe{b4f0bEBqdmO3YnH0[YQh\m:{IEeyJIhzeyCkeTDNWHMh[XO\|YYmsJGdKPTBiPTCwMlA{OyEQvF2u	NXjj[3g1RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
BA/F3	NH3ZfJJIem:5dHigbY5pcWKrdHnvckBie3OjeR?=		M1v3N\|czKGi{cx?=		NGDMcoJKdmirYnn0bY9vKG:oIFvpeEBmgG:wIEGxJIRmdGW2aX;uJEg2PTdidH:gOVU5KHKnc3nkeYV{MSCjbnSgRVgzQVBibYX0ZY51KGGwZDDZPFI{TCCvdYThcpQhMHWwa37ve44hd3KrZ3nuLUB1emGwc3\lZ5Rm\CCrbjDtc5V{\SCEQT;GN{Bk\WyuczDhd5Nme3OnZDDhd{BqdmirYnn0bY9vKG:oIHPlcIwh\3Kxd4ToJIlv[3WkYYTl[EBnd3JiN{KgbJJ{KGK7IF3UV{Bie3OjeTygS2k2OCB;IECuNFQ4KM7:TT6=	MXq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8{ODJyNES0NUc,OzB{MES0OFE9N2F-
BA/F3	NFeyfJBIem:5dHigbY5pcWKrdHnvckBie3OjeR?=		NGHDV4E4OiCqcoO=		M3[wemlvcGmkaYTpc44hd2ZiS3n0JIV5d25iMUGg[IVt\XSrb36gLFU2PyC2bzC1OVghemW\|aXT1[ZMqKGGwZDDOPFIzUyCvdYThcpQh[W6mIGm4NlNFKG23dHHueEApfW6tbn;3ckBwemmpaX6pJJRz[W6\|ZnXjeIVlKGmwIH3veZNmKEKDL1[zJINmdGy\|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigbY5kfWKjdHXkJIZweiB5MjDodpMh[nliTWTTJIF{e2G7LDDHTVUxKD1iMD6wOFkh\|ryPLh?=	NX\ld5J6RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
BA/F3	M3TJNGdzd3e2aDDpcohq[mm2aX;uJIF{e2G7		NXj2fmQ5PzJiaILz		NWH2PXFDUW6qaXLpeIlwdiCxZjDUSWwu\nW\|ZXSgVGRITlKjbIDoZUApfW6tbn;3ckBwemmpaX6pJJRz[W6\|ZnXjeIVlKGmwIH3veZNmKEKDL1[zJINmdGy\|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigbY5kfWKjdHXkJIZweiB5MjDodpMh[nliTWTTJIF{e2G7LDDHTVUxKD1iMD6wOVEh\|ryPLh?=	NHPQZZM9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9\|MEKwOFQ1OSd-M{CyNFQ1PDF:L3G+
BA/F3	NELLUFdIem:5dHigbY5pcWKrdHnvckBie3OjeR?=		M{nQ[lczKGi{cx?=		NEHYc4lKdmirYnn0bY9vKG:oIFvpeEBmgG:wIEGxJIRmdGW2aX;uJEg2PTdidH:gOVU5KHKnc3nkeYV{MSCjbnSgSFgzOEFibYX0ZY51KGGwZDDEPFIxSSCvdYThcpQhMHWwa37ve44hd3KrZ3nuLUB1emGwc3\lZ5Rm\CCrbjDtc5V{\SCEQT;GN{Bk\WyuczDhd5Nme3OnZDDhd{BqdmirYnn0bY9vKG:oIHPlcIwh\3Kxd4ToJIlv[3WkYYTl[EBnd3JiN{KgbJJ{KGK7IF3UV{Bie3OjeTygS2k2OCB;IECuNFY{KM7:TT6=	MlnHQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB{MES0OFEoRjNyMkC0OFQyRC:jPh?=
BA/F3	M4XpdGdzd3e2aDDpcohq[mm2aX;uJIF{e2G7		M1zBUFczKGi{cx?=		MlniTY5pcWKrdHnvckBw\iCNaYSg[ZhwdiBzMTDk[YxmfGmxbjCoOVU4KHSxIEW1PEBz\XOrZIXld{kh[W6mIGm4NlNFKG23dHHueEApfW6tbn;3ckBwemmpaX6pJJRz[W6\|ZnXjeIVlKGmwIH3veZNmKEKDL1[zJINmdGy\|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigbY5kfWKjdHXkJIZweiB5MjDodpMh[nliTWTTJIF{e2G7LDDHTVUxKD1iMD6wPVQh\|ryPLh?=	MmDQQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB{MES0OFEoRjNyMkC0OFQyRC:jPh?=
BA/F3	MljzS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl?		Moi1O\|IhcHK\|		NVzHe\|J[UW6qaXLpeIlwdiCxZjDLbZQhXjV4MFSgcZV1[W62IDj1cotvd3ewIH;ybYdqdilidILhcpNn\WO2ZXSgbY4hdW:3c3WgRmEwTjNiY3XscJMh[XO\|ZYPz[YQh[XNiaX7obYJqfGmxbjDv[kBk\WyuIHfyc5d1cCCrbnP1ZoF1\WRiZn;yJFczKGi{czDifUBOXFNiYYPzZZktKEeLNUCgQUAxNjFyODFOwG0v	MlznQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB{MES0OFEoRjNyMkC0OFQyRC:jPh?=
BA/F3	MXPHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>?		NULoRldEPzJiaILz		MmnyTY5pcWKrdHnvckBw\iCNaYSg[ZhwdiB7IFHZOVAzKHSxIEWwN{BqdnOncoTpc44hdXW2YX70JEh2dmuwb4fuJI9zcWerbjmgeJJidnOoZXP0[YQhcW5ibX;1d4UhSkFxRkOgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iClZXzsJIdzd3e2aDDpcoN2[mG2ZXSg[o9zKDd{IHjyd{BjgSCPVGOgZZN{[XluIFfJOVAhRSByLkGxOEDPxE1w	MkfvQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOzB{MES0OFEoRjNyMkC0OFQyRC:jPh?=
BA/F3	MmrnS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl?		MUG3NkBpenN?		M2f6W2lvcGmkaYTpc44hd2ZiS1TSJEh2dmuwb4fuJI9zcWerbjmgeJJidnOoZXP0[YQhcW5ibX;1d4UhSkFxRkOgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iClZXzsJIdzd3e2aDDpcoN2[mG2ZXSg[o9zKDd{IHjyd{BjgSCPVGOgZZN{[XluIFfJOVAhRSByLkGxOEDPxE1w	NWT1T4M6RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
GISTT1	NYG4cndmS3m2b4TvfIlkcXS7IHHzd4F6		M1\Ce\|czKGi{cx?=		NXX2TGRyS3m2b4TvfIlkcXS7IHHnZYlve3RiaIXtZY4hT0mVVGSxJINmdGy\|IHHzd4V{e2WmIHHzJINmdGxiZ4Lve5RpKGmwaHnibZRqd25iYX\0[ZIhPzJiaILzJIJ6KEOnbHzUbZRmekeubzDhd5NigSxiR1m1NEA:KDBwMUOg{txONg>?	NX3o[VlPRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMki5PVE1PjVpPkK4PVkyPDZ3PD;hQi=>
BA/F3	M{\QS2dzd3e2aDDpcohq[mm2aX;uJIF{e2G7		NXmxT\|Z6PzJiaILz		NETtRVFKdmirYnn0bY9vKG:oIFvpeEBmgG:wIEGxJIRmdGW2aX;uJEg2PTdidH:gOVU5KHKnc3nkeYV{MSCjbnSgWlY2PEFibYX0ZY51KCi3bnvuc5dvKG:{aXfpckkhfHKjboPm[YN1\WRiaX6gcY92e2ViQlGvSlMh[2WubIOgZZN{\XO\|ZXSgZZMhcW6qaXLpeIlwdiCxZjDj[YxtKGe{b4f0bEBqdmO3YnH0[YQh\m:{IEeyJIhzeyCkeTDNWHMh[XO\|YYmsJGdKPTBiPTCwMlI{OSEQvF2u	NUSxNIxKRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
BA/F3	MVnHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>?		M3eyTVczKGi{cx?=		MXzJcohq[mm2aX;uJI9nKEurdDDlfI9vKDFzIHTlcIV1cW:wIDi1OVchfG9iNUW4JJJme2mmdXXzLUBidmRiREixOmghdXW2YX70JEh2dmuwb4fuJI9zcWerbjmgeJJidnOoZXP0[YQhcW5ibX;1d4UhSkFxRkOgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iClZXzsJIdzd3e2aDDpcoN2[mG2ZXSg[o9zKDd{IHjyd{BjgSCPVGOgZZN{[XluIFfJOVAhRSByLkK5JO69VS5?	NIXDTpY9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9\|MEKwOFQ1OSd-M{CyNFQ1PDF:L3G+
GISTT1	MV3DfZRwfG:6aXPpeJkh[XO\|YYm=		NXXyXYZtPzJiaILz		M1HPfGN6fG:2b4jpZ4l1gSCjZ3HpcpN1KGi3bXHuJGdKW1SWMTDj[YxteyCqYYLic5JqdmdiS1nUJHQ3PzCLIH31eIFvfCCjc4Pld5Nm\CCjczDj[YxtKGe{b4f0bEBqdmirYnn0bY9vKGGodHXyJFczKGi{czDifUBE\WyuVHn0[ZJIdG9iYYPzZZktKEeLNUCgQUAxNjN6IN88UU4>	MV68ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQDl7MUS2OUc,Ojh7OUG0OlU9N2F-
BA/F3	MYjHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>?		NVTNVm1XPzJiaILz		MUfJcohq[mm2aX;uJI9nKFCGR1\SZYxxcGFiVkW2NWQwTDh2Mm[gcZV1[W62IDj1cotvd3ewIH;ybYdqdilidILhcpNn\WO2ZXSgbY4hdW:3c3WgRmEwTjNiY3XscJMh[XO\|ZYPz[YQh[XNiaX7obYJqfGmxbjDv[kBk\WyuIHfyc5d1cCCrbnP1ZoF1\WRiZn;yJFczKGi{czDifUBOXFNiYYPzZZktKEeLNUCgQUAxNjV{MjFOwG0v	MUe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8{ODJyNES0NUc,OzB{MES0OFE9N2F-
BA/F3	NGn0V4VIem:5dHigbY5pcWKrdHnvckBie3OjeR?=		M3HESlczKGi{cx?=		NXnjNWtXUW6qaXLpeIlwdiCxZjDLbZQhXjV4MFSvWlY2PEFibYX0ZY51KCi3bnvuc5dvKG:{aXfpckkhfHKjboPm[YN1\WRiaX6gcY92e2ViQlGvSlMh[2WubIOgZZN{\XO\|ZXSgZZMhcW6qaXLpeIlwdiCxZjDj[YxtKGe{b4f0bEBqdmO3YnH0[YQh\m:{IEeyJIhzeyCkeTDNWHMh[XO\|YYmsJGdKPTBiPTCwMlU1QSEQvF2u	M1jJXVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzNyMkC0OFQyLz5\|MEKwOFQ1OTxxYU6=
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BA/F3	MUHHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>?		NWS1OVBYPzJiaILz		NGTOc\|lKdmirYnn0bY9vKG:oIFvpeEBXPTZyRD;EPFE3UCCvdYThcpQhMHWwa37ve44hd3KrZ3nuLUB1emGwc3\lZ5Rm\CCrbjDtc5V{\SCEQT;GN{Bk\WyuczDhd5Nme3OnZDDhd{BqdmirYnn0bY9vKG:oIHPlcIwh\3Kxd4ToJIlv[3WkYYTl[EBnd3JiN{KgbJJ{KGK7IF3UV{Bie3OjeTygS2k2OCB;IECuPFM1KM7:TT6=	NV7WOYVsRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxM{CyNFQ1PDFpPkOwNlA1PDRzPD;hQi=>
BA/F3	MmDvS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl?		NGi4R2U4OiCqcoO=		MX3Jcohq[mm2aX;uJI9nKEurdDDlfI9vKDFzIHTlcIV1cW:wIDi1OlAhfG9iNUe4JJJme2mmdXXzLUBufXSjboSgLJVvc26xd36gc5Jq\2mwKTD0doFve2[nY4Tl[EBqdiCvb4Xz[UBDSS:IMzDj[YxteyCjc4Pld5Nm\CCjczDpcohq[mm2aX;uJI9nKGOnbHyg[5Jwf3SqIHnuZ5Vj[XSnZDDmc5IhPzJiaILzJIJ6KE2WUzDhd5NigSxiR1m1NEA:KDBwOUSzJO69VS5?	M4XmSVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzNyMkC0OFQyLz5\|MEKwOFQ1OTxxYU6=
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GIST430	NITjR4hEgXSxdH;4bYNqfHliYYPzZZk>		NXLYSWk{PzJiaILz		MY\DfZRwfG:6aXPpeJkh[WejaX7zeEBpfW2jbjDHTXNVPDNyIHPlcIx{KGijcnLvdolv\yCNSWSgWlY2PEFibYX0ZY51KGG\|c3Xzd4VlKGG\|IHPlcIwh\3Kxd4ToJIlvcGmkaYTpc44h[W[2ZYKgO\|IhcHK\|IHL5JGNmdGyWaYTldmdtdyCjc4PhfUwhT0l3MDC9JFMh\|ryPLh?=	MWe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQDl7MUS2OUc,Ojh7OUG0OlU9N2F-
BA/F3	NE[0V2tEgXSxdH;4bYNqfHliYYPzZZk>		NY\ES5BDPzJiaILz		MlW3R5l1d3SxeHnjbZR6KGmwIH3veZNmKHCjcnXueIFtKEKDL1[zJINmdGy\|IHnuZ5Vj[XSnZDDmc5IhPzJiaILzJIJ6KE2WUzDhd5NigSxiR1m1NEA:KDlwOUWzJO69VS5?	MYC8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8{ODJyNES0NUc,OzB{MES0OFE9N2F-
U-2 OS	M{fTSJFJXFNiYYPzZZk>				M4nyS5FJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCXLUKgU3Mh[2WubIO=	NYTzPWpRRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
A673	MmTZdWhVWyCjc4PhfS=>				M{HJNZFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCDNkezJINmdGy\|	M1TwcFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
DAOY	MmjrdWhVWyCjc4PhfS=>				NXTWOJNleUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC\|Y4Ll[Y4h\m:{IFTBU3kh[2WubIO=	MUm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR\|NUGzPUc,Ojl2M{WxN\|k9N2F-
Saos-2	NV7CcGN[eUiWUzDhd5NigQ>?				M2nZZ5FJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCVYX;zMVIh[2WubIO=	MkXrQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN\|koRjJ7NEO1NVM6RC:jPh?=
BT-37	MVrxTHRUKGG\|c3H5				NULaXItjeUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC\|Y4Ll[Y4h\m:{IFLUMVM4KGOnbHzz	NEfDOnc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+
RD	M3\hVJFJXFNiYYPzZZk>				NVjacIFDeUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC\|Y4Ll[Y4h\m:{IGLEJINmdGy\|	MX[8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR\|NUGzPUc,Ojl2M{WxN\|k9N2F-
BT-12	M4ThPZFJXFNiYYPzZZk>				M2PLXpFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCEVD2xNkBk\Wyucx?=	NWXmR2hrRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
MG 63 (6-TG R)	M2DEOJFJXFNiYYPzZZk>				M1TDd5FJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCPRzC2N{ApPi2WRzDSLUBk\Wyucx?=	MX[8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR\|NUGzPUc,Ojl2M{WxN\|k9N2F-
NB1643	NFfmfYNyUFSVIHHzd4F6				MkDqdWhVWyCxZjDw[YRq[XS{aXOgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hcWSnboTp[pkhdXWudHnwcIUhd3Cyb4L0eY5qfGmnczDmc5Ih\HK3ZzDy[ZB2enCxc3nu[\|ohWHKrbXHyfUB{[3KnZX6g[o9zKE6EMU[0N{Bk\Wyucx?=	NELtPHI9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+
OHS-50	NUHRfZhVeUiWUzDhd5NigQ>?				NHnrV3lyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiT1jTMVUxKGOnbHzz	M1POblxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
SJ-GBM2	M4HMfJFJXFNiYYPzZZk>				M3HERZFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCVSj3HRm0zKGOnbHzz	NYfRVIYzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
SK-N-MC	MnLUdWhVWyCjc4PhfS=>				NF\6WINyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiU1utUk1OSyClZXzsdy=>	NHvNSZI9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+
NB-EBc1	NXfGOIdseUiWUzDhd5NigQ>?				M3y3R5FJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCQQj3FRoMyKGOnbHzz	MWW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR\|NUGzPUc,Ojl2M{WxN\|k9N2F-
LAN-5	MlLRdWhVWyCjc4PhfS=>				NFLYcXdyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiTFHOMVUh[2WubIO=	NITDSlQ9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+
Rh18	NWq2cXdzeUiWUzDhd5NigQ>?				M{LDdJFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCUaEG4JINmdGy\|	NGXtSYM9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+

... Click to View More Cell Line Experimental Data

Assay

Methods	Test Index	PMID
Western blot	PUMA / p53; PubMed: 24763611 Clin Cancer Res WT and p53-KO HCT116 cells were treated with 40 μmol/L regorafenib for 24 hours. PUMA expression was analyzed by Western blotting. Bim / Bid / Bak / Bcl-Xl / Mcl-1; PubMed: 24763611 Clin Cancer Res The expression of indicated Bcl-2 family members was analyzed by Western blotting in HCT116 cells treated with 40 μmol/L regorafenib at indicated time points. p-p65(S536) / p65; PubMed: 24763611 Clin Cancer Res HCT116 cells were treated with 40 μmol/L regorafenib. Expression of p-p65 (S536) and β-actin at indicated time points was analyzed by Western blotting. p-FGFR2 / p-FRS2α / p-AKT / p-MAPK / p-P90RSK / FGFR2 / AKT / MAPK / p90RSK; PubMed: 29573334 Mol Oncol Changes in FGFR2 signaling molecules after regorafenib treatment. Immunoblotting assays were performed after treatment with increasing concentrations of regorafenib for 24 h. Cyclin D / Cyclin E / Cyclin A / Cyclin B / p27 / p21; PubMed: 29573334 Mol Oncol Changes in cell cycle and/or apoptosis‐related molecules. p-STAT3 / STAT3 / PARP / Caspase-9; PubMed: 25071018 Oncotarget p-STAT3(Tyr705), STAT3, the cleaved fragments of PARP and the cleaved fragments of caspase-9 were measured by western blotting at the times indicated after Hct-15 and DLD1 cells were treated with regorafenib at 5 μM. β-actin was used as a loading control. The cleaved fragments of PARP and the cleaved fragments of caspase-9 were indicated by arrows.	24763611 29573334 25071018
Immunofluorescence	p65; PubMed: 24763611 Clin Cancer Res HCT116 cells were treated with 40 μmol/L regorafenib for 3 hours and then fixed. Immunofluorescence was carried out as described in the Materials and Methods for p65 (green) and DAPI (blue). Representative pictures (400×) are shown. Arrows indicate cells with p65 nuclear translocation. F-actin / Vimentin / E-cadherin ; PubMed: 27580057 Oncotarget Immunofluorescence microscopy analysis of rhodamine phalloidin-stained F-actin, DAPI-stained nuclei, vimentin and E-cadherin in the cells.	24763611 27580057
Growth inhibition assay	GI50; PubMed: 29573334 Mol Oncol Screening of in vitro sensitivity to regorafenib in 14 gastric and 10 colorectal cancer cell lines. MTT cell proliferation assays were performed with increasing concentrations of regorafenib for 72 h. GI 50 values were averaged from at least three independent experiments in hexaplicate. Cell viability; PubMed: 25071018 Oncotarget MTT assay was performed to measure the cell viability in the colon cancer cell lines 2 days after treatment with regorafenib in a dose-dependent manner.	29573334 25071018

In vivo

Regorafenib reveals potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages in breast MDA-MB-231 and renal 786-O carcinoma models. Regorafenib prevents not only the growth of syngeneic primary 4T1 breast tumors growing orthotopically in the fat pad, but also suppresses the formation of tumor metastasis in the lung. ^[1]

Protocol

Kinase Assay:^[1]	- Collapse Kinase assays: In vitro assays using recombinant VEGFR2 (murine aa785–aa1367), VEGFR3 (murine aa818–aa1363), PDGFRβ (aa561–aa1106), Raf-1 (aa305–aa648) and BRafV600E (aa409–aa765) kinase domains are performed. Initial in vitro kinase inhibition profiling is performed at a fixed 1 μM Regorafenib concentration. Inhibitory concentration of 50% (IC50) values are determined from selected responding kinases, e.g., VEGFR1 and RET. TIE2 kinase inhibition is measured with a homogeneous time-resolved fluorescence (HTRF) assay using a recombinant fusion protein of glutathione-S-transferase, the intracellular domain of TIE2 and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate.
Cell Research:^[1]	- Collapse Cell lines: GIST 882 and TT cells Concentrations: 5 nM-10 μM Incubation Time: 96 hours Method: For proliferation assays, GIST 882 and TT cells are grown in RPMI medium containing L-glutamine, and MDA-MB-231, HepG2 and A375 cells in DMEM always containing 10% hiFBS. Cells are trypsinized, plated at 5×104 cells/well in 96-well plates in complete media containing 10% FBS and grown overnight at 37 °C. The next day, vehicle or Regorafenib serially diluted in complete growth media to between 10 μM and 5 nM final concentrations, and 0.2% DMSO, is added and incubation is continued for 96 hours. Cell proliferation is quantified. (Only for Reference)
Animal Research:^[1]	- Collapse Animal Models: Female athymic NCr nu/nu mice with Colo-205, MDA-MB-231 or 786-O Dosages: 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg Administration: Orally (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	97 mg/mL (200.9 mM)
	Water	Insoluble
	Ethanol	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 2% DMSO+30% PEG 300+5% Tween 80+ddH2O For best results, use promptly after mixing.	5mg/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 Download Regorafenib (BAY 73-4506) SDF

Molecular Weight	482.82
Formula	C₂₁H₁₅ClF₄N₄O₃
CAS No.	755037-03-7
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	Fluoro-Sorafenib, Resihance, Stivarga
Smiles	CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F

In vivo Formulation Calculator (Clear solution)

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

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mg/kg

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Step 2: Enter the in vivo formulation (Different batches have different solubility ratios, please contact Selleck to provide you with the correct ratio)

% DMSO+ % + % Tween 80+ % ddH₂O

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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.

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.

Bio Calculators

Molarity Calculator

Calculate the mass, volume or concentration required for a solution. The Selleck molarity calculator is based on the following equation:

Mass (mg) = Concentration (mM) × Volume (mL) × Molecular Weight (g/mol)

*When preparing stock solutions, please always use the batch-specific molecular weight of the product found on the via label and MSDS / COA (available on product pages).

Dilution Calculator

Calculate the dilution required to prepare a stock solution. The Selleck dilution calculator is based on the following equation:

Concentration _(start) x Volume _(start) = Concentration _(final) x Volume _(final)

This equation is commonly abbreviated as: C1V1 = C2V2 ( Input Output )

* When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and MSDS / COA (available online).

The Serial Dilution Calculator Equation

Serial Dilutions
Concertration (start):
Dilution-folds:

Computed Result

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

Molecular Weight Calculator

Enter the chemical formula of a compound to calculate its molar mass and elemental composition:

Tip: Chemical formula is case sensitive. C10H16N2O2 c10h16n2o2

Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter its chemical formula and click 'Calculate'.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Molarity Calculator

Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2021-01-06)

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT04476329	Recruiting	Drug: Regorafenib 40 MG	Hepatocellular Carcinoma	SC Liver Research Consortium LLC\|Bayer	December 15 2020	Phase 2
NCT04200404	Recruiting	Drug: CS1001\|Drug: Regorafenib	Advanced Refractory Solid Tumors	CStone Pharmaceuticals\|Bayer	December 13 2019	Phase 1\|Phase 2
NCT03793361	Recruiting	Drug: Regorafenib\|Drug: Placebo	Metastatic Soft Tissue Sarcoma	Centre Oscar Lambret	May 15 2019	Phase 2
NCT03829852	Recruiting	Drug: Regorafenib	Metastatic Colorectal Cancer	Taipei Veterans General Hospital Taiwan\|Chang Gung Memorial Hospital\|Koo Foundation Sun Yat-Sen Cancer Center	March 29 2019	--

Tech Support

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

Handling Instructions

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

If you have any other enquiries, please leave a message.

Frequently Asked Questions

Question 1:
How to resuspend Regorafenib for in vivo studies?
Answer:
For in vivo study, we recommend to use 2% DMSO+30% PEG 300+5% Tween 80+ddH2O up to 5mg/ml.

VEGFR Signaling Pathway Map

VEGFR Inhibitors with Unique Features

Selective VEGFR Inhibitors

Vandetanib (ZD6474) : VEGFR2-selective, IC50=40 nM.
Most Potent VEGFR Inhibitor

Cabozantinib (XL184, BMS-907351) : VEGFR2, IC50=0.035 nM.
FDA-approved VEGFR Inhibitor

Axitinib : Approved by FDA for Renal Cell Carcinoma.
Classic VEGFR Inhibitor

Nintedanib (BIBF 1120) : Potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM. Phase 3.

Related VEGFR Products

SU5402 ^New

SU5402 is a potent multi-targeted receptor tyrosine kinase inhibitor with IC50 of 20 nM, 30 nM, and 510 nM for VEGFR2, FGFR1, and PDGF-Rβ, respectively.
Erlotinib ^New

Erlotinib (CP358774, NSC 718781, OSI-774) is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. Erlotinib induces autophagy.
Bemcentinib (R428) ^New

Bemcentinib (R428, BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).
Axitinib

Axitinib (AG 013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM in Porcine aorta endothelial cells, respectively.

Features:Superior as second-line therapy relative to sorafenib (current standard-of-care).
Cabozantinib (BMS-907351)

Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM in cell-free assays, respectively. Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway.
Nintedanib (BIBF 1120)

Nintedanib (BIBF 1120, Intedanib, Vargatef, Ofev) is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM in cell-free assays. Phase 3.
Vandetanib (ZD6474)

Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. Vandetanib (ZD6474) increases apoptosis and induces autophagy by increasing the level of reactive oxygen species (ROS).
Lenvatinib (E7080)

Lenvatinib (E7080) is a multi-target inhibitor, mostly for VEGFR2(KDR)/VEGFR3(Flt-4) with IC50 of 4 nM/5.2 nM, less potent against VEGFR1/Flt-1, ~10-fold more selective for VEGFR2/3 against FGFR1, PDGFRα/β in cell-free assays. Lenvatinib (E7080) also inhibits FGFR1-4, PDGFR, Kit (c-Kit), RET (c-RET), and shows potent antitumor activities. Phase 3.
Pazopanib

Pazopanib (GW786034) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms/CSF1R with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively. Pazopanib induces cathepsin B activation and autophagy.
Pazopanib HCl (GW786034 HCl)

Pazopanib HCl (GW786034 HCl) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively. Pazopanib induces autophagic Type II cell death.

Features:A multi-kinase inhibitor.

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Regorafenib (BAY 73-4506)