Torin 1

Name: Torin 1
Brand: Selleck Chemicals
SKU: S2827
Rating: 5 (157 reviews)

For research use only.

Catalog No.S2827

157 publications

CAS No. 1222998-36-8

Torin 1 is a potent inhibitor of mTORC1/2 with IC50 of 2 nM/10 nM in cell-free assays; exhibits 1000-fold selectivity for mTOR than PI3K.

Selleck's Torin 1 has been cited by 157 publications

Cell Metab, 2021, S1550-4131(21)00326-0

PubMed: 34348115 ( click the link to review the publication )

Nature, 2020, 10.1038/s41586-020-03056-z

PubMed: 33328639 ( click the link to review the publication )

Cell, 2020, S0092-8674(20)31627-5

PubMed: 33338421 ( click the link to review the publication )

Cell, 2020, 25;181(7):1596-1611.e27.

PubMed: 32559461 ( click the link to review the publication )

Nat Biotechnol, 2020, 38(5):638-648

PubMed: 32249828 ( click the link to review the publication )

Cell, 2019, 177(4):896-909

PubMed: 31030999 ( click the link to review the publication )

Nat Immunol, 2018, 19(12):1330-1340

PubMed: 30420624 ( click the link to review the publication )

Cell Metab, 2018, 28(3):369-382

PubMed: 30043754 ( click the link to review the publication )

Nature, 2017, 1;546(7656):168-172.

PubMed: 28538732 ( click the link to review the publication )

Cancer Discov, 2016, 6(7):727-39

PubMed: 27231123 ( click the link to review the publication )

Nat Commun, 2021, 12(1):4789

PubMed: 34373451 ( click the link to review the publication )

Nat Commun, 2021, 12(1):3055

PubMed: 34031411 ( click the link to review the publication )

Nat Commun, 2021, 12(1):3333

PubMed: 34099704 ( click the link to review the publication )

EMBO Rep, 2021, e51329

PubMed: 33480074 ( click the link to review the publication )

Mol Syst Biol, 2021, 17(8):e10239

PubMed: 34339582 ( click the link to review the publication )

Autophagy, 2021, 1-19

PubMed: 34282994 ( click the link to review the publication )

Autophagy, 2021, 1-14

PubMed: 33749521 ( click the link to review the publication )

Autophagy, 2021, 1-11

PubMed: 33993848 ( click the link to review the publication )

Autophagy, 2021, 1-22

PubMed: 33890549 ( click the link to review the publication )

Cell Death Discov, 2021, 7(1):201

PubMed: 34349107 ( click the link to review the publication )

Front Immunol, 2021, 12:682627

PubMed: 34140952 ( click the link to review the publication )

J Inflamm Res, 2021, 14:3969-3983

PubMed: 34429629 ( click the link to review the publication )

J Cell Mol Med, 2021, 25(12):5729-5743

PubMed: 33949118 ( click the link to review the publication )

Sci Rep, 2021, 11(1):14111

PubMed: 34239027 ( click the link to review the publication )
Front Microbiol, 2021, 12:596874

PubMed: 33935983 ( click the link to review the publication )

Cell Signal, 2021, 80:109912

PubMed: 33388443 ( click the link to review the publication )

Front Physiol, 2021, 12:650055

PubMed: 34177609 ( click the link to review the publication )

Biochem Biophys Res Commun, 2021, 567:154-160

PubMed: 34157442 ( click the link to review the publication )

iScience, 2021, 24(7):102778

PubMed: 34278273 ( click the link to review the publication )

Nat Cell Biol, 2020, 22(10):1170-1179

PubMed: 32989246 ( click the link to review the publication )

Sci Transl Med, 2020, 12(548):eaay5691

PubMed: 32554707 ( click the link to review the publication )

Mol Cell, 2020, S1097-2765(20)30786-3

PubMed: 33271062 ( click the link to review the publication )

Nat Commun, 2020, 11(1):5842

PubMed: 33203880 ( click the link to review the publication )

Nat Commun, 2020, 24;11(1):479

PubMed: 31980602 ( click the link to review the publication )

Autophagy, 2020, 15:1-13

PubMed: 32264736 ( click the link to review the publication )

Dev Cell, 2020, 55(3):298-313.e10

PubMed: 33171110 ( click the link to review the publication )

Cell Rep, 2020, 30(5):1400-1416

PubMed: 32023458 ( click the link to review the publication )

Cell Rep, 2020, 30(6):1835-1847

PubMed: 32049014 ( click the link to review the publication )

Cell Death Differ, 2020, 10.1038/s41418-020-00646-2

PubMed: 33100324 ( click the link to review the publication )

Cancers (Basel), 2020, 12(12)E3766

PubMed: 33327544 ( click the link to review the publication )

PLoS Pathog, 2020, 9;16(6):e1008568

PubMed: 32516328 ( click the link to review the publication )

Cell Death Dis, 2020, 8;5:e1214

PubMed: 24810050 ( click the link to review the publication )

Br J Cancer, 2020, 22

PubMed: 32439931 ( click the link to review the publication )

Mol Nutr Food Res, 2020, 1;e1901231

PubMed: 32476238 ( click the link to review the publication )

Am J Cancer Res, 2020, 10(12):4488-4497

PubMed: 33415013 ( click the link to review the publication )

J Immunol, 2020, ji2000244

PubMed: 32989095 ( click the link to review the publication )

Mol Cancer Res, 2020, 10.1158/1541-7786

PubMed: 32169890 ( click the link to review the publication )

Int J Mol Sci, 2020, 24;21(6) pii: E2240

PubMed: 32213867 ( click the link to review the publication )
Front Med (Lausanne), 2020, 7:591736

PubMed: 33644083 ( click the link to review the publication )

Exp Cell Res, 2020, 10.1016/j.yexcr.2020.111981

PubMed: 32234375 ( click the link to review the publication )

Exp Eye Res, 2020, 203:108421

PubMed: 33359326 ( click the link to review the publication )

Cell Rep Med, 2020, 1(8):100131

PubMed: 33294856 ( click the link to review the publication )

J Clin Invest, 2020, 137585

PubMed: 32673292 ( click the link to review the publication )

Emerg Microbes Infect, 2020, 9(1):1748-1760

PubMed: 32691695 ( click the link to review the publication )

J Biol Chem, 2020, jbc.RA120.13703

PubMed: 32683324 ( click the link to review the publication )

bioRxiv, 2020, 2020.10.09.334128

PubMed: 33052348 ( click the link to review the publication )

Oxid Med Cell Longev, 2020, 2020:1364147

PubMed: 32724488 ( click the link to review the publication )

J Cell Physiol, 2020, 10.1002/jcp.30172

PubMed: 33230821 ( click the link to review the publication )

Nat Metab, 2020, 2(1):41-49

PubMed: 31993556 ( click the link to review the publication )

bioRxiv, 2020, 10.1101/2020.11.18.388306

PubMed: None ( click the link to review the publication )

Cancer Res, 2020, 80(3):444-457

PubMed: 31722999 ( click the link to review the publication )

Mol Cell, 2019, 73(4):788-802

PubMed: 30704899 ( click the link to review the publication )

Nat Commun, 2019, 10(1):4741

PubMed: 31628323 ( click the link to review the publication )

Nat Commun, 2019, 10(1):1693

PubMed: 30979895 ( click the link to review the publication )

Nat Commun, 2019, 10(1):5681

PubMed: 31831743 ( click the link to review the publication )

Autophagy, 2019, 15(3):493-509

PubMed: 30304977 ( click the link to review the publication )

Autophagy, 2019, 1-13

PubMed: 30957628 ( click the link to review the publication )

Autophagy, 2019, 10.1080/15548627.2019.1703353

PubMed: 31847700 ( click the link to review the publication )

Autophagy, 2019, 10.1080/15548627.2019.1628536

PubMed: 31203721 ( click the link to review the publication )

Proc Natl Acad Sci U S A, 2019, 10.1073/pnas.1911393116

PubMed: 31732667 ( click the link to review the publication )

Cell Rep, 2019, 29(3):589-602

PubMed: 31618629 ( click the link to review the publication )

Cell Rep, 2019, 27(7):2075-2091.e5

PubMed: 31091447 ( click the link to review the publication )
Cell Mol Immunol, 2019, 10.1038/s41423-019-0281-6

PubMed: 31467416 ( click the link to review the publication )

Oncogene, 2019, 38(10):1639-1650

PubMed: 30337688 ( click the link to review the publication )

Oncogene, 2019, 10.1038/s41388-019-1085-y

PubMed: 31685947 ( click the link to review the publication )

Oncogene, 2019, 38(2):209-227

PubMed: 30087437 ( click the link to review the publication )

EBioMedicine, 2019, 40:151-162

PubMed: 30711516 ( click the link to review the publication )

Cell Death Dis, 2019, 10(6):399

PubMed: 31113939 ( click the link to review the publication )

Lab Invest, 2019, 99(5):648-658

PubMed: 30679758 ( click the link to review the publication )

Biochem Pharmacol, 2019, 162:191-201

PubMed: 30471247 ( click the link to review the publication )

J Biol Chem, 2019, 294(10):3760-3771

PubMed: 30617181 ( click the link to review the publication )

Life Sci, 2019, 232:116665

PubMed: 31323273 ( click the link to review the publication )

Biochem Biophys Res Commun, 2019, 519(4):909-915

PubMed: 31563324 ( click the link to review the publication )

Nat Commun, 2018, 9(1):4831

PubMed: 30446646 ( click the link to review the publication )

Nat Commun, 2018, 9(1):5426

PubMed: 30575721 ( click the link to review the publication )

Nat Commun, 2018, 9(1):2819

PubMed: 30026551 ( click the link to review the publication )

J Pathol, 2018, 245(2):235-248

PubMed: 29570219 ( click the link to review the publication )

PLoS Genet, 2018, 14(5):e1007369

PubMed: 29750810 ( click the link to review the publication )

Development, 2018, 145(18)

PubMed: 30126904 ( click the link to review the publication )

J Immunol, 2018, 200(8):2826-2834

PubMed: 29563176 ( click the link to review the publication )

Lung Cancer, 2018, 120:34-45

PubMed: 29748013 ( click the link to review the publication )

Mol Cancer Res, 2018, 16(4):599-609

PubMed: 29330285 ( click the link to review the publication )

Exp Cell Res, 2018, 363(1):84-94

PubMed: 29289595 ( click the link to review the publication )

Braz J Med Biol Res, 2018, 51(6):e7080

PubMed: 29694502 ( click the link to review the publication )

Cell Res, 2017, 27(2):184-201

PubMed: 27934868 ( click the link to review the publication )

Mol Cell, 2017, 67(6):907-921

PubMed: 28844862 ( click the link to review the publication )
Mol Cell, 2017, 65(6):1029-1043

PubMed: 28306502 ( click the link to review the publication )

Nat Commun, 2017, 8:15045

PubMed: 28429794 ( click the link to review the publication )

Nat Commun, 2017, 8;8:15617

PubMed: 28593995 ( click the link to review the publication )

Autophagy, 2017, 13(8):1364-1385

PubMed: 28598230 ( click the link to review the publication )

Autophagy, 2017, 13(4):686-702

PubMed: 28121484 ( click the link to review the publication )

J Cell Biol, 2017, 216(6):1567-1577

PubMed: 28442534 ( click the link to review the publication )

PLoS Pathog, 2017, 13(3):e1006249

PubMed: 28249048 ( click the link to review the publication )

Cell Death Dis, 2017, 8(8):e2970

PubMed: 28771229 ( click the link to review the publication )

Sci Rep, 2017, 7(1):1994

PubMed: 28515443 ( click the link to review the publication )

Sci Rep, 2017, 7(1):13832

PubMed: 29062139 ( click the link to review the publication )

J Biol Chem, 2017, 292(35):14544-14555

PubMed: 28684424 ( click the link to review the publication )

Am J Physiol Cell Physiol, 2017, 313(5):C501-C515

PubMed: 28794108 ( click the link to review the publication )

J Agric Food Chem, 2017, 65(31):6625-6637

PubMed: 28697598 ( click the link to review the publication )

Radiat Res, 2017, 187(3):382-396

PubMed: 28327001 ( click the link to review the publication )

Oncotarget, 2017, 8(65):109848-109856

PubMed: 29312653 ( click the link to review the publication )

Oncotarget, 2017, 8(55):93688-93703

PubMed: 29212182 ( click the link to review the publication )

Oncotarget, 2017, 8(52):89527-89538

PubMed: 29163768 ( click the link to review the publication )

Oncotarget, 2017, 8(65):109848-109856

PubMed: 29312653 ( click the link to review the publication )

Oncotarget, 2017, 8(27):44550-44566

PubMed: 28562352 ( click the link to review the publication )

Protein Cell, 2016, 7(12):878-887

PubMed: 27909983 ( click the link to review the publication )

Aging (Albany NY), 2016, 8(12):3535-3551

PubMed: 28077803 ( click the link to review the publication )

Stem Cells Transl Med, 2016, 5(5):580-90

PubMed: 27025692 ( click the link to review the publication )

ACS Chem Biol, 2016, 11(5):1428-37

PubMed: 26938669 ( click the link to review the publication )

Mol Biol Cell, 2016, 27(2):321-33

PubMed: 26582390 ( click the link to review the publication )
J Biol Chem, 2016, 291(33):17467-77

PubMed: 27339899 ( click the link to review the publication )

J Cell Physiol, 2016, 10.1002/jcp.25456

PubMed: 27301841 ( click the link to review the publication )

Front Plant Sci, 2016, 7:1746

PubMed: 27917191 ( click the link to review the publication )

BMC Musculoskelet Disord, 2016, 17:150

PubMed: 27052304 ( click the link to review the publication )

Oncotarget, 2016, 7(5):5521-37

PubMed: 26575168 ( click the link to review the publication )

Oncotarget, 2016, 7(34):55690-55703

PubMed: 27494886 ( click the link to review the publication )

Oncotarget, 2016, 7(36):57525-57544

PubMed: 27438153 ( click the link to review the publication )

J Clin Invest, 2015, 125(3):1174-88

PubMed: 25664849 ( click the link to review the publication )

Elife, 2015, 4

PubMed: 25846574 ( click the link to review the publication )

J Med Chem, 2015, 58(16):6559-73

PubMed: 26237138 ( click the link to review the publication )

Cell Commun Signal, 2015, 13:15

PubMed: 25849580 ( click the link to review the publication )

J Cell Physiol, 2015, 230(5):1064-74

PubMed: 25283437 ( click the link to review the publication )

Mol Cancer Res, 2015, 13(2):223-30

PubMed: 25582703 ( click the link to review the publication )

J Virol, 2015, 89(1):626-42

PubMed: 25339775 ( click the link to review the publication )

Sci Rep, 2015, 5:13891

PubMed: 26403635 ( click the link to review the publication )

J Biol Chem, 2015, 10.1074/jbc.M114.621706

PubMed: 25878248 ( click the link to review the publication )

J Biol Chem, 2015, 290(9):5592-605

PubMed: ( click the link to review the publication )

J Biol Chem, 2015, 290(9):5592-605

PubMed: 25561726 ( click the link to review the publication )

Cell Signal, 2015, 27(8):1557-68

PubMed: 25936523 ( click the link to review the publication )

BMC Cancer, 2015, 15:855

PubMed: 26542945 ( click the link to review the publication )

PLoS One, 2015, 10(8):e0135614

PubMed: 26267903 ( click the link to review the publication )

Oncotarget, 2015, 6(27):23238-48

PubMed: 26177051 ( click the link to review the publication )

PLoS Pathog, 2014, 10(6):e1004196

PubMed: 24945378 ( click the link to review the publication )

Cell Death Dis, 2014, 5:e1214

PubMed: 24810050 ( click the link to review the publication )
Am J Pathol, 2014, 184(1):214-29

PubMed: 24215913 ( click the link to review the publication )

J Biol Chem, 2014, 289(43):29739-49

PubMed: 25164809 ( click the link to review the publication )

J Biol Chem, 2014, 289(25):17830-42

PubMed: 24798333 ( click the link to review the publication )

Mol Cell Biol, 2014, 34(24):4474-84

PubMed: 25288641 ( click the link to review the publication )

Biochem Biophys Res Commun, 2014, 10.1016/j.bbrc.2014.05.047

PubMed: 24858682 ( click the link to review the publication )

Oncotarget, 2014, 5(24):12715-27

PubMed: 25587030 ( click the link to review the publication )

Oncotarget, 2014, 5(16):6816-31

PubMed: 25149175 ( click the link to review the publication )

Oncotarget, 2014, 5(18):8737-49

PubMed: 25228590 ( click the link to review the publication )

Blood, 2013, 121(18):3619-30

PubMed: 23444404 ( click the link to review the publication )

Trends Microbiol, 2013, 21(6):286-95

PubMed: 23608036 ( click the link to review the publication )

Genes Dev, 2013, 27(10):1115-31

PubMed: 23699409 ( click the link to review the publication )

PLoS One, 2013, 8(11):e80070

PubMed: 24244612 ( click the link to review the publication )

EMBO Mol Med, 2011, 3(4):189-200

PubMed: 21412983 ( click the link to review the publication )

Purity & Quality Control

Choose Selective mTOR Inhibitors

Biological Activity

Description

Torin 1 is a potent inhibitor of mTORC1/2 with IC50 of 2 nM/10 nM in cell-free assays; exhibits 1000-fold selectivity for mTOR than PI3K.

Targets

mTORC1 ^[1] (Cell-free assay)	mTOR ^[2] (Cell-free assay)	DNA-PK ^[2] (Cell-free assay)	mTORC2 ^[1] (Cell-free assay)	p110γ ^[2] (Cell-free assay)	View More
2 nM	4.32 nM	6.34 nM	10 nM	171 nM	View More

In vitro

Torin1 inhibits phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. ^[1] ^[2] Torin1 causes cell cycle arrest through a rapamycin-resistant mechanism that is also independent of mTORC2. Torin1 disrupts mTORC1-dependent phenotypes more completely than rapamycin. Rapamycin-resistant functions of mTORC1 are required for cap-dependent translation. ^[1] In a recent study, it is reported Torin1 increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON. ^[3]

Cell Data

Cell Lines	Assay Type	Activity Description	PMID
ETK-1	NX[yPW9QT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NH2xTFFKSzVyPUCuNFAxOzB4IN88US=>	MWe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
OCUB-M	MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NVT2cmNXUUN3ME2wMlAxOTl2IN88US=>	NF3kfo89[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
DOHH-2	NHHMUYdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NFjqeGhKSzVyPUCuNFAzOjVizszN	NHf0ToQ9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
NOS-1	MlzMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M4DSXmlEPTB;MD6wNFI1OiEQvF2=	NFTnO4E9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
L-363	MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MV7JR\|UxRTBwMECyPFQh\|ryP	NHrUSFM9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
RL95-2	NEjWdHpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M37ZRmlEPTB;MD6wNFMzKM7:TR?=	NFXHeWw9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
BL-70	MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MnzsTWM2OD1yLkCwN\|M4KM7:TR?=	MXq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
TGBC1TKB	MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NHmw[nRKSzVyPUCuNFA{PzlizszN	NF2wbVg9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
697	NXvsNYgyT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M4KwVWlEPTB;MD6wNFY{PCEQvF2=	NHXGcZo9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
RPMI-8226	NFm5PFBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NFz6co5KSzVyPUCuNFA3PTFizszN	MlnvQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
BL-41	NX7PRmNUT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M37lfGlEPTB;MD6wNFY6PiEQvF2=	Moi0QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
MRK-nu-1	MkDqS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M1rpZWlEPTB;MD6wNFcxPyEQvF2=	MV:8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
EW-1	Mlv1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NHPic3JKSzVyPUCuNFA4PDlizszN	NGj0PJE9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
EVSA-T	M{HRVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NIHNd5VKSzVyPUCuNFA5QTJizszN	MYq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
HUTU-80	MkT2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MXnJR\|UxRTBwMEC5Nlkh\|ryP	M3L4NlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
VA-ES-BJ	M1[5[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	M3i5R2lEPTB;MD6wNFk5PCEQvF2=	MWO8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
GCIY	M{[zVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MXrJR\|UxRTBwMEGwNFch\|ryP	MXm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
ES6	MmLmS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NGHKXWJKSzVyPUCuNFExQDNizszN	NYnhc\|VPRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
NALM-6	MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MYfJR\|UxRTBwMEGxNFIh\|ryP	MlfYQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
LB996-RCC	MnXaS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NUm2fWxkUUN3ME2wMlAyOTN5IN88US=>	NWPMZ3hYRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
EW-16	MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M{HPdGlEPTB;MD6wNVE6OiEQvF2=	M3jxNVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
KALS-1	NFe4R\|dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NULocFRGUUN3ME2wMlAyOTl6IN88US=>	M3\RfFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
OPM-2	NW\pU4RsT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	Mo\oTWM2OD1yLkCxNlkh\|ryP	MlnxQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
KU812	MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M2rmS2lEPTB;MD6wNVI6PiEQvF2=	NH;SVVU9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
A4-Fuk	NUT0N2N7T3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MVfJR\|UxRTBwMEGzNVkh\|ryP	MkH0QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
KGN	M{XLfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	M{XHe2lEPTB;MD6wNVM2QSEQvF2=	MmfuQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
KS-1	MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NHvFXItKSzVyPUCuNFE{QTJizszN	M{DlcVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
no-11	NULjc2pmT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MUnJR\|UxRTBwMEGzPVUh\|ryP	NGHLO5g9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
PSN1	NGTucJBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MX\JR\|UxRTBwMEG0NFkh\|ryP	NHqxXXo9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
SK-LMS-1	M{LsUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NXLjRpB[UUN3ME2wMlAyPDF\|IN88US=>	NWrOXZV2RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
LS-411N	NH:wcItIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MnnLTWM2OD1yLkCxOFM6KM7:TR?=	MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
HT-144	MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NV7NTZVEUUN3ME2wMlAyPDVzIN88US=>	M3HpU\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
ACN	MmfrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NFnQVHpKSzVyPUCuNFE2KM7:TR?=	NYL3WW4xRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
RKO	MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MU\JR\|UxRTBwMEG1N\|Mh\|ryP	M{S2U\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
CMK	MnTsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MXPJR\|UxRTBwMEG1OFMh\|ryP	MnHxQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
GB-1	NF3JNFBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	Mn\zTWM2OD1yLkCxOVU{KM7:TR?=	MmLaQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
KE-37	NH;1U2FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M37ZXWlEPTB;MD6wNVU4OyEQvF2=	NUPmW5djRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
no-10	M{nuN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NYrXNIhyUUN3ME2wMlAyPTh2IN88US=>	NHHKbHk9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
MOLT-16	M2Lxfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NFPJb3JKSzVyPUCuNFE3OjJizszN	Moe4QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
HEL	NXLhcZpCT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	Mn3YTWM2OD1yLkCxOlQh\|ryP	M12xPFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
NCI-H1355	Ml;RS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M1;lfmlEPTB;MD6wNVY1PiEQvF2=	MX68ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
IST-MEL1	NFnqbVhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NWPIU3JCUUN3ME2wMlAyPzd2IN88US=>	NWTWOVRIRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
MHH-PREB-1	MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M1XDemlEPTB;MD6wNVgyQCEQvF2=	MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
ES8	NH[1XoZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NHG2OZpKSzVyPUCuNFE5PDRizszN	NFrxeZU9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
LC-2-ad	M3Lmdmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	Mn3kTWM2OD1yLkCyNVM4KM7:TR?=	Ml65QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
LAMA-84	NWrZcGZlT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M{XzPWlEPTB;MD6wNlE3PyEQvF2=	M{\zfFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
BV-173	M1XNWWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MWHJR\|UxRTBwMEKyNFMh\|ryP	M4TyVlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
SW872	NV7ab5VsT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M1XIbWlEPTB;MD6wNlI1PyEQvF2=	NX3NO494RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
SK-UT-1	MlfpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MYXJR\|UxRTBwMEKyOlEh\|ryP	NWr1RVB5RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
OS-RC-2	NWfFbnRbT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M1TWRmlEPTB;MD6wNlMzOyEQvF2=	NX;BdWx6RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
NCI-H747	NHvQWIJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NGHVZY1KSzVyPUCuNFI{OyEQvF2=	NF7QPHk9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
MZ2-MEL	NEfleZRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NE\jbFlKSzVyPUCuNFI{OzdizszN	NVPJbZkzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
TE-11	M3izeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NEPIOIdKSzVyPUCuNFI{PzJizszN	NETaW2k9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
KURAMOCHI	MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NGrvdFlKSzVyPUCuNFI1OTRizszN	NYTaOHRvRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:ve5d4NmWkaT7hZ{52cy:laHXtZoww[2:vcH;1coRgemWyb4L0Y4NiemRxQ1jFUWJNOTJ3NkS1PU8oRlODTlfFVlww[T5?
HD-MY-Z	MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NWjoUWFIUUN3ME2wMlAzPDJ4IN88US=>	M3PDS\|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
GI-1	MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NFryRmtKSzVyPUCuNFI1PjlizszN	MnPJQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
LB1047-RCC	NIDTS49Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NXPrenNQUUN3ME2wMlAzPDh6IN88US=>	NFzs[5A9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
TE-12	MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NGjMXYhKSzVyPUCuNFI2PSEQvF2=	MljVQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
MZ7-mel	NFOyVo5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MmTJTWM2OD1yLkCyOlA6KM7:TR?=	NHL6WHY9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
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A101D	NXPUU4g3T3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MlnFTWM2OD1yLkCyOlUh\|ryP	MYW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
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LC-1F	MW\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NVLkempkUUN3ME2wMlA{QTh7IN88US=>	MVm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
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Daudi	Mm\SS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M1GzOWlEPTB;MD6wOFIzPSEQvF2=	MWq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:5d4eu[YJqNmGlLoXrM4Np\W2kbD;jc41xd3WwZG;y[ZBwenShY3Hy[E9EUEWPQlyxNlU3PDV7Lze+V2FPT0WUPD;hQi=>
SW982	NInRXYJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NH;jXWNKSzVyPUCuNFQzPDZizszN	NFniO\|A9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;3e5cv\WKrLnHjMpVsN2OqZX3icE9kd22yb4Xu[H9z\XCxcoTfZ4Fz\C:FSFXNRmwyOjV4NEW5M{c,W0GQR1XSQE9iRg>?
SF126	MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MlzFTWM2OD1yLkC0N\|YyKM7:TR?=	Ml3KQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xd4f3MoVjcS6jYz71b{9kcGWvYnyvZ49ueG:3bnTfdoVxd3K2X3PhdoQwS0iHTVLMNVI2PjR3OT:nQnNCVkeHUkyvZV4>
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COLO-684	NF3jN3FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M1rF[WlEPTB;MD6wOFU3OSEQvF2=	M2DPcFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
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HCC1599	M{TqNWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	Ml;tTWM2OD1yLkC0PFc6KM7:TR?=	M{j4eFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4f3e{5m[mlwYXOueYsw[2inbXLsM4NwdXCxdX7kY5JmeG:{dG;jZZJlN0OKRV3CUFEzPTZ2NUmvK\|5USU6JRWK8M4E,
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BT-37	M4jwNJFJXFNiYYPzZZk>	NXnHfZRKeUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC\|Y4Ll[Y4h\m:{IFLUMVM4KGOnbHzz	NWTtU2RuRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
OHS-50	NGXLOZByUFSVIHHzd4F6	MkGxdWhVWyCxZjDw[YRq[XS{aXOgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hcWSnboTp[pkhdXWudHnwcIUhd3Cyb4L0eY5qfGmnczDmc5Ih\HK3ZzDy[ZB2enCxc3nu[\|ohWHKrbXHyfUB{[3KnZX6g[o9zKE:KUz21NEBk\Wyucx?=	MoLhQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN\|koRjJ7NEO1NVM6RC:jPh?=
Rh41	M1yyS5FJXFNiYYPzZZk>	NHXl[m5yUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiUni0NUBk\Wyucx?=	MknNQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN\|koRjJ7NEO1NVM6RC:jPh?=
SJ-GBM2	NIf0dZJyUFSVIHHzd4F6	M3W3VZFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCVSj3HRm0zKGOnbHzz	NYHKcYg2RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
SK-N-MC	M3nlOZFJXFNiYYPzZZk>	NEXiTZZyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiU1utUk1OSyClZXzsdy=>	MV28ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR\|NUGzPUc,Ojl2M{WxN\|k9N2F-
NB-EBc1	MYDxTHRUKGG\|c3H5	NGDXfo9yUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiTlKtSWJkOSClZXzsdy=>	NWeyTHF{RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC\|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N\|UyOzlpPkK5OFM2OTN7PD;hQi=>
SK-N-MC	MXPxTHRUKGG\|c3H5	NVuxfJNveUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiQ3;u[olzdWG2b4L5JJNkemWnbjDmc5IhW0tvTj3NR{Bk\Wyucx?=	NH2wb3o9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N\|UyOzl:L3G+
TC32	MonCdWhVWyCjc4PhfS=>	NFnlNWJyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCFb37mbZJu[XSxcomgd4Nz\WWwIH\vdkBVSzN{IHPlcIx{	M1;SdFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=

... Click to View More Cell Line Experimental Data

Assay

Methods	Test Index	PMID
Western blot	ATF4 / p-S6K(T389) / S6K / p-eIF2α(S51) / eIF2α / 4EBP1 / eIF3b; PubMed: 28494858 Cell Rep 4E-BPs are required for mTOR control of ATF4. 4E-BP1/2 wild-type (WT), double knockout (DKO), or DKO MEFs stably expressing 4ebp1 (DKO + 4ebp1) were treated with vehicle (DMSO) or 250 nM Torin 1 for 4 hr. Cell extracts were analyzed by immunoblotting for the indicated proteins. LC3 / p62 / PARP / pAKT(S473) / p4EBP1(S65) / pS6K1(T389) / pS6(S235/236); PubMed: 24126619 Int J Oncol Cells were treated with increasing doses of the mTOR inhibitors, torin 1 (A) and rapamycin (B), in RPMI-1640 containing 10% FBS for 2 days. LC3 processing, p62 accumulation, PARP cleavage, AKT phosphorylation and mTOR pathway activity (indicated by phosphorylation of 4E-BP, S6K1 and S6) were analyzed by western blotting of total cell lysates. GAPDH was the control for protein loading. p-mTOR(S2481) / mTOR / rictor / Sin1 / p-Akt S473 / p-Akt T450 / p-Akt T308 / p-S6K1 T389 / S6K1; PubMed: 21965657 J Biol Chem mTOR kinase activity controls abundance of SIN1. MDA-MB-435 cells were incubated with specific mTOR inhibitor (0.5 μm TORIN) for 24 or 48 h and analyzed. Vinculin / p-S6; PubMed: 28757207 Mol Cell A375 cells were treated with Torin1 for 48 h and localization of proteins was visualized by confocal microscopy. Scale bar, 50 μm. Focal adhesion size was measured by Fiji program.	28494858 24126619 21965657 28757207
Immunofluorescence	lipin-1; PubMed: 28347999 FASEB J Inhibition of mTOR activity promoted the nuclear translocation of lipin-1. After treatment with or without torin 1 for 4 h, cells expressing HA-lipin-1 were fixed and stained with a rabbit HA antibody followed by Alexa 594–conjugated goat anti-rabbit secondary antibody. Nuclei were stained with DAPI. Scale bars, 20 μM.	28347999
Growth inhibition assay	Cell viability; PubMed: 28757207 Mol Cell Cancer cell lines were grown in complete media with/without mTOR inhibitor, Torin1 (250 nM). Media and Torin1 were replaced every 2 days and cells were counted at the indicated time points. Data are the means ± SD of three separate experiments performed in triplicate.	28757207

In vivo

Torin1 is efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrates good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. ^[2]

Protocol

Kinase Assay:^[1]	- Collapse mTORC1 and mTORC2 in Vitro Kinase Assays: To produce soluble mTORC1, HEK-293T cell lines that stably express N-terminally FLAG-tagged Raptor are generated using vesicular stomatitis virus G-pseudotyped MSCV retrovirus. For mTORC2, similar HeLa cells that stably express N-terminally FLAG-tagged Protor-1 are generated. Both complexes are purified by lysing cells in 50 mm HEPES, pH 7.4, 10 mm sodium pyrophosphate, 10 mm sodium β-glycerophosphate, 100 mm NaCl, 2 mm EDTA, 0.3% CHAPS. Cells are lysed at 4 °C for 30 min, and the insoluble fraction is removed by microcentrifugation at 13,000 rpm for 10 min. Supernatants are incubated with FLAG-M2 monoclonal antibody-agarose for 1 h and then washed three times with lysis buffer and once with lysis buffer containing a final concentration of 0.5 M NaCl. Purified mTORC1 is eluted with 100 μg/mL 3×FLAG peptide in 50 mm HEPES, pH 7.4, 100 mm NaCl. Eluate can be aliquoted and stored at -80 °C. Substrates S6K1 and Akt1 are purified. Kinase assays are performed for 20 min at 30 °C in a final volume of 20 μL consisting of the kinase buffer (25 mm HEPES, pH 7.4, 50 mm KCl, 10 mm MgCl₂, 500 μm ATP) and 150 ng of inactive S6K1 or Akt1 as substrates. Reactions are stopped by the addition of 80 μL of sample buffer and boiled for 5 min. Samples are subsequently analyzed by SDS-PAGE and immunoblotting.
Cell Research:^[1]	- Collapse Cell lines: MEFs Concentrations: ~250 nM Incubation Time: 4 days Method: Cell viability is assessed with the CellTiter-Glo Luminescent Cell Viability Assay. On Day 0, 96-well plates are seeded with 500 cells per well and grown overnight. On Day 1, cells are treated with the appropriate compounds and subsequently analyzed on Days 3-5. For analysis, plates are incubated for 60 min at room temperature; 50 μL of CellTiter-Glo reagent is added to each well, and plates are mixed on an orbital shaker for 12 min. Luminescence is quantified on a standard plate luminometer. (Only for Reference)
Animal Research:^[2]	- Collapse Animal Models: U87MG xenograft model Dosages: 20 mg/kg Administration: Administered via i.p. once daily (Only for Reference)

References

[4] Dowling RJ, et al, Science, 2010, 328(5982), 1172-1176.

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Solubility (25°C)

In vitro	DMSO	2 mg/mL warmed (3.29 mM)
	Water	Insoluble
	Ethanol	Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download Torin 1 SDF

Molecular Weight	607.62
Formula	C₃₅H₂₈F₃N₅O₂
CAS No.	1222998-36-8
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	N/A
Smiles	CCC(=O)N1CCN(CC1)C2=C(C=C(C=C2)N3C(=O)C=CC4=CN=C5C=CC(=CC5=C43)C6=CC7=CC=CC=C7N=C6)C(F)(F)F

In vivo Formulation Calculator (Clear solution)

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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.

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

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The Serial Dilution Calculator Equation

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Computed Result

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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

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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 re-constitute the inhibitor for i.p. administration?
Answer:
S2827 Torin 1 can be dissolved in 5% DMSO/30% PEG 300/ddH2O at 0.25 mg/ml clearly, and in 10% DMSO/corn oil at 0.5 mg/ml, it is also a clear solution.

mTOR Signaling Pathway Map

mTOR Inhibitors with Unique Features

Selective mTOR inhibitor

Rapamycin (Sirolimus) : mTORC1-selective, IC50=~0.1 nM.
Most Potent mTOR Inhibitor

Rapamycin (Sirolimus) : mTOR, IC50=~0.1 nM.
FDA-approved mTOR Inhibitor

Temsirolimus (CCI-779, NSC 683864) : Approved by FDA for Renal Cell Carcinoma (RCC).
Newest mTOR Inhibitor

XL388 ^New : Highly potent, selective, ATP-competitive inhibitor of mTOR with IC50 of 9.9 nM, 1000-fold selectivity over the closely related PI3K kinases.

Related mTOR Products

MHY1485 ^New

MHY1485 is a potent, and cell-permeable mTOR activator, and also potently inhibits autophagy.
CHIR-99021 (CT99021) ^New

CHIR-99021 (CT99021) is a GSK-3α and GSK-3β inhibitor with IC50 of 10 nM and 6.7 nM, respectively. CHIR99201 does not exhibit cross-reactivity against cyclin-dependent kinases (CDKs) and shows a 350-fold selectivity toward GSK-3β compared to CDKs. CHIR99021 functions as a Wnt/β-catenin activator and induces autophagy.
Dorsomorphin (Compound C) ^New

Dorsomorphin (Compound C, BML-275) is a potent, reversible, selective AMPK inhibitor with K_i of 109 nM in cell-free assays, exhibiting no significant inhibition of several structurally related kinases including ZAPK, SYK, PKCθ, PKA, and JAK3. Dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6. Dorsomorphin is used in promoting specific cell differentiation and inducing cancer cell line autophagy. For animal testing, the water-soluble S7306 Dorsomorphin (Compound C) 2HCl is recommended.
Rapamycin (AY-22989)

Rapamycin (AY-22989, Rapamune, Sirolimus, NSC-2260804) is a specific mTOR inhibitor with IC50 of ~0.1 nM HEK293 cells.
Everolimus (RAD001)

Everolimus (RAD001, SDZ-RAD) is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay. Everolimus induces cell apoptosis and autophagy and inhibits tumor cells proliferation.
AZD8055

AZD8055 is a novel ATP-competitive mTOR inhibitor with IC50 of 0.8 nM in MDA-MB-468 cells with excellent selectivity (∼1,000-fold) against PI3K isoforms and ATM/DNA-PK. AZD8055 induces caspase-dependent apoptosis and also induces autophagy. Phase 1.

Features:First drug to inhibit both types of mTOR protein.
Temsirolimus (CCI-779)

Temsirolimus (CCI-779, NSC 683864) is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus induces autophagy and apoptosis.
Sapanisertib (MLN0128)

Sapanisertib (MLN0128, INK 128, TAK-228) is a potent and selective mTOR inhibitor with IC50 of 1 nM in cell-free assays; >200-fold less potent to class I PI3K isoforms, superior in blocking mTORC1/2 and sensitive to pro-invasion genes (vs Rapamycin). Phase 1.
Tacrolimus (FK506)

Tacrolimus (FK506, FR900506, Fujimycin, Prograf) is a 23-membered macrolide lactone, it reduces peptidyl-prolyl isomerase activity in T cells by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. Tacrolimus also inhibits the phosphatase activity of calcineurin. Tacrolimus induces vascular endothelial autophagy.
KU-0063794

KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM in cell-free assays; no effect on PI3Ks.

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Torin 1