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(12) Patent Application Publication (10) Pub. No.: US 2009/0186358 A1 Melville Et Al US 200901 86.358A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0186358 A1 Melville et al. (43) Pub. Date: Jul. 23, 2009 (54) PATHWAYANALYSIS OF CELL CULTURE Related U.S. Application Data PHENOTYPES AND USES THEREOF (60) Provisional application No. 61/016,390, filed on Dec. 21, 2007. (75) Inventors: Mark Melville, Melrose, MA (US); Publication Classification Niall Barron, Shankill (IE): Martin Clynes, Clontarf (IE): (51) Int. C. CI2O I/68 (2006.01) Padraig Doolan, Swords (IE): CI2P 2L/00 (2006.01) Patrick Gammell, Naas (IE): C07K I4/00 (2006.01) Paula Meleady, Ratoath (IE) CI2O 1/02 (2006.01) CI2N I/2 (2006.01) Correspondence Address: CI2N 5/06 (2006.01) CHOATE, HALL & STEWART LLP CI2N 5/04 (2006.01) TWO INTERNATIONAL PLACE (52) U.S. Cl. .............. 435/6; 435/69.1:530/300; 435/29: BOSTON, MA 02110 (US) 435/252.3; 435/325; 435/419:435/254.2 (57) ABSTRACT (73) Assignees: Wyeth, Madison, NJ (US); Dublin The present invention provides methods for systematically City University, Glasnevin (IE) identifying genes, proteins and/or related pathways that regu late or indicative of cell phenotypes. The present invention further provides methods for manipulating the identified (21) Appl. No.: 12/340,629 genes, proteins and/or pathways to engineer improved cell lines and/or to evaluate or select cell lines with desirable (22) Filed: Dec. 19, 2008 phenotypes. inhibition of Signalling Signalling Caspases Apoptosis Apoptosis Signalling Caspases ATM Integrin MAPK p38 Signalling Signalling Signalling Signalling Signalling MAPK in ATM p53 Integrin Signalling Signalling Apoptosis Growth and Caspases Signalling Different. Death p53 Inhibition of RBumOur Apoptosis Signalling Receptor Caspases Signalling Apoptosis Suppressor Pathway Analysis Patent Application Publication Jul. 23, 2009 Sheet 1 of 50 US 2009/0186358 A1 | 1 || 2 || 3 || 4 || 5 || p53 ATM inhibition of MAPK HCGR1 Signalling Signalling Caspases Apoptosis Apoptosis Signalling ATM Integrin MAPK p38 HCGR2 SignallingP. Caspases Signalling Signalling Signalling Signalling p53 MAPK in Integrin HCGR3 Signalling Signalling Apoptosis Growth and Caspases Signalling Different. p53 ReceptP" inhibition of RB Tumour HCGR4 Apoptosis Signalling r Apoptosis Suppressor Caspases Pathway Analysis FIG. I. Patent Application Publication Jul. 23, 2009 Sheet 2 of 50 US 2009/0186358 A1 fears sea -- a r --- r = r s or Upregulated in B19 >1.5-Fold) Fatty Acid Degradation w Acetyl-CoA wy. HMGCS1 Cholesterol HMG-CoA HMGCR 7-dehydro Cholesterol Mevalonate Lathosterol Mevalonate-5-P Mevalonate-5-P CYP51A1 MVD Lanosterol DiMethylally-PP D1 Delta Isopentenyl-5-PP LSS O . -- FDPS -> Geranyl-PP-D FDPS Squalene-2,3-Epoxide trans-trans-farnesyl-PP SOLE FDFT1 -> Squalene Patent Application Publication Jul. 23, 2009 Sheet 3 of 50 US 2009/0186358 A1 Figure 3A To Fig 3B Butanoate - SHCV Butanoate Metabolism a - - - - - - - - - - - - - - - - Glutamate Metabolism L-Glutamate 4-Aminobutanoate1 -1 semialdehydeSuccinate Vinylacetyl-CoA4-Hydroxy Y butanoate Vitamin B6 Metabolism 1. Poly-B-hydroxy- PHBC butyrate (R)-3-(R)-3-Hydroxy butanoyloxybutanoate (R)-3-Hydroxy butanoate Synthesis and Degradation O-------------- of Ketone Bodies Patent Application Publication Jul. 23, 2009 Sheet 4 of 50 US 2009/0186358 A1 (S.S.)-Butane O23-diol O1176 C) (S)-Acetoin Figure 3B i 15 Dae O O5,124ar Thiamine diphosphate i iacety 12 45 ? ir O b-HO- O-HéV-4 i (R,R)-Butane-2,3-diol (R)-Acetoin 2-Acetolactate 2-(a-Hydroxyethyl2. W) 2.2.1.6 Pyruvate !------------ ------thiamine diphosphate----------- Old----- O 1.1.1.83 glycolysis Ho-O O O O Gluconeogenesis Final 4.2.1.31 (R)-Malate O) Butanoylphosphate 2.3.1.19 12.1.10?)M O ButanalO u> 12.15 sad Biosynthesis of Type || ry Polyketide Backbone 1399.2UU13.144 ar 5.333 Crotopyl-CoA GlutaConyl-1-CoA 1.2.7.1 O O23,154 ( ) r) O Of glutaryl-CoA2-Hydroxy i 4.1.1.70 4.2.1 ^ 'R)-3-hydroA. U42,117ar O 2.83.12 butany, as (S)-3-Hydroxy O) 2-Hydroxyglutarate O butanoyl-CoA ar O)1.1992 D. D. D. D. D. D D O O Or 1.1.1.35 2-Oxoglutarate Glutamate S2 Pyruvate Metabolism ^ CMA in a 2.3.19 ACeacetyl-CoA ^ ise 0 -o 2.3.3.10 Up (S)-3-Hydroxy-3- methylglutaryl-CoA From Fig3A Patent Application Publication Jul. 23, 2009 Sheet 5 of 50 US 2009/0186358 A1 Citrate Cycle TO i.......................-O- Fr. DO FIG. 4B : Butanoate Metabolism Pyruvate Metabolism 6.4.1.1 Guanasion O 5,2Glycoly------ GIWColysis/Gluconeocenesis 9 o-O utamate Metabolism ...' ... O-...i 4.1.132O - i < Lysiner Degradation. -O Fatty MitochondriaAcid Elongation Aspartate Metabolism O £: .." i. p-O O PEP ..." Fatty Acid Biosynthesis O-.................. 4.1149 / . o Glyoxylate and A. Aceyl-CoA ...". OFatty Acid Metabolism Dicarboxylate Metabolism : M-Oxaloacetate 233.1O2 O- R-2 1.1.1.37 wawr O Dr(S)-Malate COAY 4.2.1.2 (3S)-Citryl-CoArax v ar r 2.83.10 Fumarate ...-O.D.O..................... -O Tyrosine "... Urea Cycle Acetyl-CoA i Metabolism “........O 135.1 Arginine and ThP Down Proline Metabolism SPPopanoate metabolism 6.2.1.4 DOWn Succinyl-CoA (2.3.1.61 O O O 1.24.2 3-Carboxy-1-hydroxy ) propyl-ThPP Lipoamide Dihydrolipoamide 18.14 To FIG. 4. Citrate Cycle - SHCV FIG. 4A Patent Application Publication Jul. 23, 2009 Sheet 6 of 50 US 2009/0186358 A1 From FG, 4A river.......................................: 4.2.13 cis-ACOnitate 4.2.13 form. 1.1.141 : Waline, Phenylalanine, Leucine Metabolism CD CD and isoleucine Degradation is a n an a Ya as a a a gri 2-Oxoglutarate "..."... "..... 9 :... "...r. -O ... Lysine Biosynthesis ...............O t ASCOrbate and Aldarate .. Metabolism ... "...r.O * Glutamate Metabolism 12.73 D-glutamine..............rO and D-glutamate Metabolism From FIG. 4A Citrate Cycle - SHCV FIG. 4B Patent Application Publication Jul. 23, 2009 Sheet 7 of 50 US 2009/0186358 A1 9."ADIAH | | CD O 6000 Patent Application Publication Jul. 23, 2009 Sheet 8 of 50 US 2009/0186358A1 Gram-neqative E. To Fig 6B Hepatocyte-mediated TNF-a excretion of LPS in bile Cytoplasm r RAk' siTPECCO-G TAF6 MEKK TAK1 OMKK47 RXRo ProteaSOme sac, E, Nucleus BRMA i TNFo -------- -7--------- \ is Ble acid JNK1/2-le-C. Radic FF assic HL NRO E. 1N c-Ju 5. SS-e (a -ar 63: 5. EcoS 322 & 3) 7 NCYPAY E. APOE ABCA1 ABCG5 OEP(O PLTP NROB2 PUUUS APOC2 OAP8 PLTP MRP2 UUUOAP4 APOC ABCG1 ABCG8 SR-B SREBP1 APOE BSEP MPR2 OATP2 NTCP 124 Genes involved in cholesterol Bile acid Genes involved in lipid Genes involved in and lipid metabolism and biosynthesis metabolism fatty acid bile acid and lipid transport bile acid and organic Organic anion anion transport transport LPS-IL-1 - SHCV Figure 6A Patent Application Publication Jul. 23, 2009 Sheet 9 of 50 US 2009/0186358 A1 From Fig 6A Figure 6B - ACOX FABP ACSDOW MRP3 CYP288 MRP2 CYP4A22 HMGCS FATP CPT ove Hems G Heme Up A Biosynthesis Biosynthesis Fatty acid Fatty acid iors & O 3 UoAIP2 cyPaca, 6 O: MOR3 Oxidation and lipid PGss GT - PAPSS2 UGT OAP2 ior. SUT GSTUp TMRP4 CYP2C9 G SULT GSTUp N. 1transport i.e.CYP2C metabolizingPhase II transportersSS orc? metabolizingPhase PhaseUABCB9 Fatty acid loyee enzymes CYP3A4 enzymes transporters and lipid i b Xenobiotic and e metabolism - CYP3A5 r;e xeOOOCG olranspo an XenobioticOrganic anion and i CYP metabolism CYP3Af metabolism transport O CES MGMT e. MACOO sonica CAT FMO O FMCO Phase 1 Phase metabolizing enzymes metabolizing enzymes Lipid and Lipid and Xenobiotic xenobiotic metabolism metabolism Patent Application Publication Jul. 23, 2009 Sheet 10 of 50 US 2009/0186358A1 Figure 7A NRF-2 Mediated Oxidative Stress Response - SHCV NRF2-mediated Oxidative Stress Response Drugs UV radiation inflammatory cytokines Xenobiotics lonizing Prostiglandins Antioxidansoxidants radation Growth factors Chemopreventive Agents Low density lipoproteins Bacterial and viral infections No o6. Heavy metals Oxidative stress Cytoplasm Metabolism Electrophiles (s MEKK ; ASK1 TAK1 PKC 5 OMKK36 AKT ER streSS ERK1,2O iO p$2s/S PERK SeSK3B NRF2 P andubiquitination proteasomal C N 8.ter REE degradation CUL3 NC'sC Rocí P COKEAR Actin NRF2CO (97 N ONRE2^Actin Nucleus Patent Application Publication Jul. 23, 2009 Sheet 11 of 50 US 2009/0186358 A1 From Fig 7A ERK 1/2 small BACH1 MAF CBP/p300 Actin C-FOS CO OS Jun NRF2 FRA COATF4 C-MAF NRF2 aree3 Lic se ARE/EpRE CO C NRF2 small SQSMCOTCO MAF PSMO ATF4 UB2R1C. &PRDXHO-1 WCP e OFTL USP14 (C UBBO CFTH HSP HIP2CO SR-B1 MRP1 (CAT Ubiquitination OS?, Phase I (e. and detoxifying GPX2 Proteasomal O proteins degradationproteins O EP d SODU p CCT7 O Transport of TXN Xenobiotics CLPP (C and e metabolites GSR FKPB5 (e. e e TRXR1 PPB Cl Antioxidant ERP29Up proteins Chaperone nd St Reduction of proteins Repair and removal of Phase and damaged metabolizing enzymes proteins c/ Y Detoxification of xenobiotics Reactive Metabolism of Xenobiotics metabolites Fl9. e 7B Cell Survival Tumorigenesis Patent Application Publication Jul. 23, 2009 Sheet 12 of 50 US 2009/0186358 A1 CD----->{)} 8"OICH Patent Application Publication Jul. 23, 2009 Sheet 13 of 50 US 2009/0186358 A1 RR-R-RRRCSSR-R-R-R-R-S-RRRRR RR-R-R-R-R-R-R-R-RRRR ------------------------arrass---2 s Sa--- series) CCCCCCCCCCCCCCCCCCCCOOOOOOOOOOCO2C DOCSOOOOOOOOOOOOOO Apoptosis Eda-A1 FIG. 9 Patent Application Publication Jul. 23, 2009 Sheet 14 of 50 US 2009/0186358 A1 RRSR RSR-S-S-S-S-I-R R W ------------8-8-8-8-4CCCCCCCCCCCCCCCCCCCCCCCCCCOOOCOOCOCOOOOOOC leasleek S. Eda-A2 FIG. I0 Patent Application Publication Jul. 23, 2009 Sheet 15 of 50 US 2009/0186358 A1 To FIG 11 Alanine and Aspartate Metabolism Glycolysis Gluconeogenesis CO Pyruvate Alanine and Aspartate Metabolism -HCD FIG.
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