DOCSLIB.ORG

Supplementary Figure S1 Tdf Binding Assay for SCH772984, Vertex 11E and GSK1120212

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Supplementary Figure S1 Tdf Binding Assay for SCH772984, Vertex 11E and GSK1120212 Supplementary Figure S1 TdF binding assay for SCH772984, Vertex 11e and GSK1120212 ERK + 5uM GSK1120212 ERK + 5uM SCH772984 Tm = -0.15 ± 0.20 Tm = 10.3 ± 0.30 KD = NBidiNo Binding KD = 0240.24 ± 0140.14 n M Protein + 5uM Compound Protein + 5uM Compound Protein only Protein only ERK + 5uM Vertex 11e MEK + 5uM GSK1120212 Tm =68= 6.8 ± 131.3 Tm =80= 8.0 ± 0510.51 K = 5.4 ± 2.2 nM D KD = 7.1 ± 2.7 nM Protein + 5uM Compound Protein + 5uM Compound Protein only Protein only MEK + 5uM SCH772984 MEK + 5uM Vertex 11e Tm = -0.17 ± 0.14 Tm = -0.11 ± 0.13 KD = No Binding KD = No Binding Protein + 5uM Compound Protein only Protein + 5uM Compound Protein only Supplementary Figure S1 (cont.) p-ERK + 5uM GSK1120212 Tm = 0.23 ± 0.31 KD = No Binding Protein + 5uM Compound Protein only P-ERK + 5uM SCH772984 Tm = 9.8 ± 0.23 KD = 0.19 ± 0.12nM Protein + 5uM Compound Protein only p-ERK + 5uM Vertex 11e Tm =10.3 ± 1.3 KD = 0110.11 ± 0. 062nM Protein + 5uM Compound Protein only Supplementary Figure S2 Inhibition of BRAF inhibitor-induced phosphorylation of ERK by SCH772984 in HCT-116 colorectal and Calu-6 non-small cell lung cancer lines Calu-6 HCT-116 PLX4720 10uM 1uM- 10uM 1uM - 10uM 1uM- 10uM 1uM - 772984 --- + + + --- + + + 300nM pERK tERK pMEK tMEK 1 2 3 4 5 6 7 8 9 10 11 12 Supplementary Figure S3 Time course of pRSK & pERK suppression in A375 cells treated with SCH772984 or control (DMSO) A375 BRAFV600E melanoma 2hrs 6hrs 16hrs 24hrs 36hrs SCH772984 2uM _ + _ + _ + _ + _ + pRSK RSK pERK ERK pCRAF CRAF pMEK MEK pBRAF BRAF Actin Supplementary Figure S4 Supplementary Figure S5 Flow Cytometry Analysis of BRAF mutant cell lines (LOX) treated with SCH772984 A No drug 24h 48h M1 = M1 = 0.8% 2 % 0 50 100 150 200 250 0 50 100 150 200 250 Channels (FL2-A-FL2-Area) Channels (FL2-A-FL2-Area) B SCH772984 24h 48h M1 = M1 = 20% 9 % 0 50 100 150 200 250 0 50 100 150 200 250 Channels (FL2-A-FL2-Area) Channels (FL2-A-FL2-Area) Supplementary Figure S6 Treatment of BRAF inhibitor resistant RKO colorectal cell lines with SCH772984 or GSK1120212 (MEK inhibitor) BRAFi-resistant, BRAF-mutant RKO colorectal RKO RKO RKO RKO BR (Acquired NRASG12C) RKO BR (Acquired NRASG12C) RKO BR (Acquired NRASG12C) 140 140 140 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 Viability (% control) Viability (% control) 20 20 Viability (% control) 20 0 0 0 0 -9 -8 -7 -6 -5 -4 0 -9 -8 -7 -6 -5 -4 0 -9 -8 -7 -6 -5 -4 PLX4032 log [M] GSK1120212 log [M] SCH772984 log [M] Relative mRNA expression 0.0 0.2 0.4 0.6 0.8 1.0 121 . 2 By SCH772984 in BRAF-mutan in SCH772984 By A375 untreated Transcriptional inhibitionof several ERK target genes Transcriptional DUSP6 A375 DMSO A375 PLX4032 A375 SCH772984 A375BR PLX4032 24 hr 18 hr 6 hr A375BR SCH772984 Supplementary Figure S7 0.0 0.2 040 0.6 0.8 1.0 1.2 141 . 4 4 A375 untreated A375 DMSO MYC A375 PLX4032 A375 SCH772984 A375BR PLX4032 A375BR SCH772984 t melanomacellline(A375) 121 0.0 0.2 0.4 0.6 0.8 1.0 . 2 A375 untreated A375 DMSO LIF A375 PLX4032 A375 SCH772984 A375BR PLX4032 A375BR SCH772984 606 0.0 1.0 2.0 3.0 4.0 5.0 . 0 A375 untreated A375 DMSO IL8 A375 PLX4032 A375 SCH772984 A375BR PLX4032 A375BR SCH772984 Supplementary Figure S8 Cell lines overexpressing constitutively active MEK1 respond to SCH772984 A A375 + RFP A375 + MEK1 F129L 120 120 ) 100 100 80 80 60 60 40 40 ability (% control ability i 20 20 V 0 0 0 -9 -8 -7 -6 -5 -4 0 -9 -8 -7 -6 -5 -4 PLX4032 log [M] SCH772984 log [M] B A375 + RFP A375 + MEK1 DD 120 120 100 100 80 80 control) 60 60 40 40 20 20 Viability (% 0 0 0 -9 -8 -7 -6 -5 -4 0 -9 -8 -7 -6 -5 -4 PLX4032 log [M] SCH772984 log [M] Supplementary Figure S9 Real-time proliferation assay of RKO dual resistant cell line in the presence of SCH772984 BRAFi + MEKi combination resistance in BRAF-mutant colorectal RKO RKO A B parental BR + MR RKO parental (IncuCyte) PLX4032 (10 uM) + + + + GSK1120212 (1 uM) + + + + DMSO SCH772984 (1 uM) + ++ pMEK MEK pERK ERKi ERK BRAFi+MEKi BRAFi+MEKi+ERKi pRSK (light) pRSK (dark) RSK RKO BR+MR (I ncuC yt e) GAPDH BRAFi+MEKi DMSO C IC50 for SCH772984 in 5-day viability assay (ViaLight) Tumor line SCH772984 IC50 (nM) ERKi RKO parental 11 BRAFi+MEKi+ERKi RKO BR+MR (with 13 PLX4032+GSK1120212) RKO BR+MR (without 44 PLX4032+GSK1120212) Supplementary Figure S10 Dual resistant cell lines A101D exhibit increased levels of proteins that include BRAF, CRAF, PDGFRB and phosphorylated AKT Parental A101D A101D BR + MR BRAF CRAF IGF1Rβ PDGFRB pAKT S473 AKT Actin Supplementary Table S1 Invitro Kinase profile of SCH772984 in a panel of 309 kinases Kinases with ≥50% inhibition at 1 uM SCH772984 (% inhibition) CLK2 (65%) FLT4 (VEGFR3) 60% GSG2 (Haspin) 51% MAP4K4 (HGK) 71% MAPK1 (ERK2) 100% MINK1 66% PRKD1 (PKC mu) 50% TTK* 62% Kinases with <50% inhibition at 1 uM SCH772984 ABL1, ABL1 E225K, ABL1 G250E, ABL1 T315I, ABL1 Y253F, ABL2, ACVR1*, ACVR1B, ADRBK1, ADRBK2, AKT1, AKT2, AKT3, ALK, AMPKA1/B1/G1, AMPKA2/B1/G1, AURKA, AURKB, AURKC, AXL, BLK, BMPR1A*, BMX, BRAF*, BRAFV599E*, BRSK1, BTK, CAMK1, CAMK1D, CAMK2A, CAMK2B, CAMK2D, CAMK4, CAMKK1*, CAMKK2*, CDC42BPA, CDC42BPB, CDK1/cycB, CDK2/cycA, CDK5/p25, CDK5/p35, CDK4/cycH/MNAT1, CDK8/cycC*, CDK9/cycK*, CDK9/cycT1, CHEK1, CHEK2, CHUK, CLK1, CLK3, cRAF, CSF1R, CSK, CSNK1A1, CSNK1D, CSNK1E, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL2, DDR2*, DMPK*, DNA-PK, DYRK1A, DYRK1B, DYRK3, DYRK4, EEF2K, ERBB1, ERBB1 L858R, ERBB1 L861Q, ERBB1 T790M, ERBB1 T790M L858R, EPHA1, EPHA2, EPHA4, EPHA5, EPHA7*, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2, ERBB4, FER, FES (FPS), FGFR1, FGFR2, FGFR3, FGFR3 K650E, FGFR4, FGR, FLT1, FLT3, FLT3 D835Y, FRAP1, FRK, FYN, GRK4, GRK5, GRK6, GRK7, GSK3A , GSK3B , HCK, HIPK1, HIPK2, HIPK4, IGF1R , IKBKB, IKBKE, INSR, INSRR, IRAK1, IRAK4, ITK, JAK1, JAK2, JAK2 JH1 JH2, JAK2 JH1 JH2 V617F, JAK3, KDR, KIT, KIT T670I, KIT V654A*, LCK, LIMK1*, LIMK2*, LTK, LYNA, LYNB, MAP2K1 (MEK1)*, MAP2K1 S218D S222D*, MAP2K2 (MEK2)*, MAP2K3 (MEK3)*, MAP2K6 (MKK6), MAP2K6 (MKK6)*, MAP2K6 (MKK6) S207E T211E*, MAP3K10 (MLK2)*, MAP3K11 (MLK3)*, MAP3K14 (NIK)*, MAP3K2 (MEKK2)*, MAP3K3 (MEKK3)*, MAP3K5 (ASK1)*, MAP3K7/MAP3K7IP1 (TAK1-TAB1)*, MAP3K9 (MLK1), MAP4K2 (GCK), MAP45 ( KHS 1), MAPK8 (J NK1), MAPK9 (J NK2), MAPKAPK2, MAPKAPK3, MAPKAPK5 (PRAK), MARK1, MARK2, MARK3, MARK4, MATK, MELK, MERTK, MET, MET M1250T, MKNK1, MLCK*, MST1R, MST4, MUSK, MYLK*, MYLK2, NEK1, NEK2, NEK4, NEK6, NEK7, NEK9, NLK*, NTRK1, NTRK2, NTRK3, NUAK1, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PASK, PDGFRA, PDGFRA D842V, PDGFRA T574I, PDGFRB, PDK1, PDK1 Direct, PHKG1, PHKG2, PI4KA, PI4KB, PIK3C2A, PIK3C2B, PIK3C3, PIK3CA/PIK3R1, PIK3CD/PIK3R1, PIK3CG, PIM1, PIM2, PKN1, PLK1, PLK2, PLK3, PRKACA, PRKCA, PRKCB1, PRKCB2, PRKCD, PRKCE, PRKCG, PRKCH, PRKCI, PRKCN, PRKCQ, PRKCZ, PRKD2 , PRKG1 , PRKG2 , PRKX , PTK2 , PTK2B, PTK6, RAF1 Y340D Y341D*, RET, RET V804L, RET Y791F, RIPK2*, ROCK1, ROCK2, ROS1, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RPS6KB1, SGK, SGK2, SGKL, SLK*, SNF1LK2, SPHK1, SPHK2, SRC, SRC N1, SRMS, SRPK1, SRPK2, STK16*, STK17A*, STK22B, STK22D, STK23, STK24, STK25, STK3, STK33*, STK4, SYK, TAOK2, TAOK3*, TBK1, TEC*, TEK, TGFBR1*, TNK2*, TXK, TYK2, TYRO3, WEE1*, WNK2*, YES1, ZAK*, ZAP70 *Denotes binding assay (rather than activity assay) Supplementary Table S2 In vitro efficacy of SCH772984 in tumor cell line panel SCH 772984 Cell line Type EC50 (nM) Ras BRAF BRAF Status Malme 3M Melanoma 10 WT V600E Homozygous WM-266-4 Melanoma 20 WT V600D Heterozygous UACC-62 Melanoma 30 WT V600E Homozygous Colo-205 Colon 36 WT V600E Homozygous SK-Mel-1 Melanoma 37 WT V600E Heterozygous WiDr Colon 39 WT V600E Heterozygous M14 Melanoma 47 WT V600E Heterozygous HT-29 Colon 50 WT V600E Heterozygous 8505C Thyroid 50 WT V600E Heterozygous WM-115 Melanoma 60 WT V600D Heterozygous HT-144 Melanoma 60 WT V600E Homozygous SK-Mel-5 Melanoma 66 WT V600E Heterozygous A375-SM Melanoma 75 WT V600E Homozygous SK-Mel-28 Melanoma 85 WT V600E Homozygous LOX Melanoma 100 WT V600E Homozygous SK-Mel-3 melanoma 118 WT V600E Heterozygous K1 Thyroid 130 WT V600E Heterozygous Hs-695T Melanoma 165 WT V600E Heterozygous 8305C Thyroid 170 WT V600E Homozygous BHT-101 Thyroid 300 WT V600E Heterozygous RPMI-7951 Melanoma 344 WT V600E Heterozygous A2058 Melanoma 360 WT V600E Heterozygous SK-Hep-1 Liver 1422 WT V600E Heterozygous A673 Rhabdomyosarcoma 3001 WT V600E Heterozygous DBTRG-05MG CNS 3001 WT V600E Hetero SW-626 Ovarian 33 Kras G12V WT LoVo Colon 47 Kras G13D WT MiaPaCa Pancreas 53 Kras G12C WT SW-620 Colon 104 Kras G12V WT CAPAN-1 Pancreas 104 Kras G12V WT SW-527 Breast 121 Kras G12V WT HCT-116 Colon 128 Kras G13D WT SW-480 Colon 165 Kras G12V WT HPAC Pancreas 170 Kras G12D WT OVCAR-5 Ovarian 208 Kras G12V WT AsPc-1 Pancreas 270 Kras G12D WT A549 NSCLC 326 KG12SKras G12S WT SNU-1 Gastric 354 Kras G12D WT HOP62 NSCLC 676 Kras G12C WT H23 NSCLC 1000 Kras G12C WT Cal 62 Thyroid 1000 Kras G12R WT MB-231 Breast 1000 Kras G13D G464V SU.86.86 Pancreas 1001 Kras G12D WT CFPAC-1 Pancreas 1001 Kras G12V WT A427 NSCLC 1433 Kras G12D WT MDAH-2774 Ovarian 2657 Kras G12V WT NCI-H157 Lung 3000 Kras G12R WT HTB-177 NSCLC 3000 Kras Q61H WT UM-UC-3 Bladder 3001 Kras G12C WT HCT-8 Colon 3001 Kras G12D WT Panc-1 Pancreas 3001 Kras G12D WT DLD-1 Colon 3001 Kras G13D WT HCT-15 Colon 3001 Kras G13D WT HL-60 Leukemia 30 Nras Q61L WT SK-Mel-2 Melanoma 34 Nras Q61R WT RD Rhabdomyosarcoma 123 Nras Q61H WT HT-1197 Bladder 316 Nras Q61R WT Molt-3 Leukemia 600 Nras G12C - PA-1 Ovarian 1001 Nras G12D WT Molt-4 Leukemia 3001 Nras G12C WT Supplementary Table S2 (continued) Hs 700T panc/intest 50 - WT NCI-H292 Lung 90 WT WT A2780
Load more

Recommended publications
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic
    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int.
    [Show full text]
  • Involvement of the PRKCB1 Gene in Autistic Disorder
    Molecular Psychiatry (2009) 14, 705–718 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp ORIGINAL ARTICLE Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression C Lintas1,2,14, R Sacco1,2,14, K Garbett3, K Mirnics3,4, R Militerni5, C Bravaccio6, P Curatolo7, B Manzi7, C Schneider8, R Melmed9, M Elia10, T Pascucci11,12, S Puglisi-Allegra11,12, K-L Reichelt13 and AM Persico1,2 1Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy; 2Laboratory of Molecular Psychiatry and Psychiatric Genetics, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy; 3Department of Psychiatry, Vanderbilt University, Nashville, TN, USA; 4Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA; 5Department of Child Neuropsychiatry, II University of Naples, Naples, Italy; 6Department of Child Neuropsychiatry, University ‘Federico II’, Naples, Italy; 7Department of Child Neuropsychiatry, University ‘Tor Vergata’, Rome, Italy; 8Center for Autism Research and Education, Phoenix, AZ, USA; 9Southwest Autism Research and Resource Center, Phoenix, AZ, USA; 10Unit of Neurology and Clinical Neurophysiopathology, I.R.C.C.S. ‘Oasi Maria S.S.’, Troina (EN), Italy; 11Department of Psychology, University ‘La Sapienza’, Rome, Italy; 12Laboratory of Behavioral Neurobiology, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy and 13Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and bII isoenzymes result from the alternative splicing of the PKCb gene (PRKCB1), previously found to be associated with autism.
    [Show full text]
  • PRODUCTS and SERVICES Target List
    PRODUCTS AND SERVICES Target list Kinase Products P.1-11 Kinase Products Biochemical Assays P.12 "QuickScout Screening Assist™ Kits" Kinase Protein Assay Kits P.13 "QuickScout Custom Profiling & Panel Profiling Series" Targets P.14 "QuickScout Custom Profiling Series" Preincubation Targets Cell-Based Assays P.15 NanoBRET™ TE Intracellular Kinase Cell-Based Assay Service Targets P.16 Tyrosine Kinase Ba/F3 Cell-Based Assay Service Targets P.17 Kinase HEK293 Cell-Based Assay Service ～ClariCELL™ ～ Targets P.18 Detection of Protein-Protein Interactions ～ProbeX™～ Stable Cell Lines Crystallization Services P.19 FastLane™ Structures ～Premium～ P.20-21 FastLane™ Structures ～Standard～ Kinase Products For details of products, please see "PRODUCTS AND SERVICES" on page 1～3. Tyrosine Kinases Note: Please contact us for availability or further information. Information may be changed without notice. Expression Protein Kinase Tag Carna Product Name Catalog No. Construct Sequence Accession Number Tag Location System HIS ABL(ABL1) 08-001 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) BTN BTN-ABL(ABL1) 08-401-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ABL(ABL1) [E255K] HIS ABL(ABL1)[E255K] 08-094 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) HIS ABL(ABL1)[T315I] 08-093 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) [T315I] BTN BTN-ABL(ABL1)[T315I] 08-493-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ACK(TNK2) GST ACK(TNK2) 08-196 Catalytic domain
    [Show full text]
  • Supplementary Table S1. Kinase Selectivity of MPI-0479605. (A)
    A B In-house kinase profiling Invitrogen SelectScreen Profiling % % % Kinase IC50 ( M) Kinase IC50 ( M) inhibition inhibition inhibition AKT3 >5 IKK-epsilon >5 Kinase at 500 nM Kinase at 500 nM Kinase at 500 nM ALK 0.26 INSR 0.38 ABL1 7 GRK6 -7 PAK1 4 AUR-A >5 JAK1 >5 GRK2 4 HCK 7 PASK 6 AUR-B >5 JNK1 0.11 AKT1 2 HIPK2 9 PHKG1 8 AUR-C >5 MEK1 >5 AXL 6 HIPK4 -6 PRKCB1 -2 B-RAF 3.2 MST4 >5 BMX 14 IGF1R 37 PRKCE 0 CDK1 >5 NEK2 >5 BRSK1 -9 IRAK4 0 PRKCG 3 CDK2 >5 PDK1 >5 CAMK2D -1 ITK 9 PRKCI -2 CDK6 >5 PKA >5 CDC42 BPA 0 LCK 29 PRKCN 6 CHK1 >5 PKC-delta >5 CDK5/p25 -1 LIMK1 17 PRKCZ -5 CHK2 >5 PLK1 >5 CSF1R 82 MAP2K1 11 PRKG2 2 C-MET >5 PLK4 3.3 CSK 1 MAP2K6 2 PTK6 15 C-SRC >5 ROCK2 >5 CSNK1D 10 MAP3K3 17 RET 11 DYRK2 >5 RSK2 >5 CSNK1G1 -1 MAP3K5 -1 RPS6KA2 23 ERK2 3.9 STK33 1.1 CSNK2A2 33 MAP3K8 12 RPS6KA5 2 FAK1 2.7 TAK1 >5 DCAMKL2 2 MAPK1 0 SGK2 4 FER 0.59 TAO1 >5 DYRK1B 1 MAPK11 2 SNF1LK2 3 FLT3 0.080 TBK1 >5 EEF2K 2 MAPK12 5 SRPK2 -3 HGK >5 TRKB >5 EGFR 14 MAPK3 -2 STK22B 11 IKK-alpha >5 YES1 >5 EPHA1 6 MAPK9 61 STK23 -1 IKK-beta >5 EPHA4 -10 MAPKAPK2 9 STK24 -2 EPHB1 -33 MARK4 3 STK25 0 ERBB2 5 MELK 6 TEK 6 FGFR1 15 MERTK 7 TYK2 10 FGR 17 MKNK1 2 TYRO3 -2 FLT4 15 MST1R 3 ZAP70 5 FRAP1 7 NEK1 1 GRK4 3 NEK4 -6 Supplementary Table S1.
    [Show full text]
  • Gene Symbol Accession Alias/Prev Symbol Official Full Name AAK1 NM 014911.2 KIAA1048, Dkfzp686k16132 AP2 Associated Kinase 1
    Gene Symbol Accession Alias/Prev Symbol Official Full Name AAK1 NM_014911.2 KIAA1048, DKFZp686K16132 AP2 associated kinase 1 (AAK1) AATK NM_001080395.2 AATYK, AATYK1, KIAA0641, LMR1, LMTK1, p35BP apoptosis-associated tyrosine kinase (AATK) ABL1 NM_007313.2 ABL, JTK7, c-ABL, p150 v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1) ABL2 NM_007314.3 ABLL, ARG v-abl Abelson murine leukemia viral oncogene homolog 2 (arg, Abelson-related gene) (ABL2) ACVR1 NM_001105.2 ACVRLK2, SKR1, ALK2, ACVR1A activin A receptor ACVR1B NM_004302.3 ACVRLK4, ALK4, SKR2, ActRIB activin A receptor, type IB (ACVR1B) ACVR1C NM_145259.2 ACVRLK7, ALK7 activin A receptor, type IC (ACVR1C) ACVR2A NM_001616.3 ACVR2, ACTRII activin A receptor ACVR2B NM_001106.2 ActR-IIB activin A receptor ACVRL1 NM_000020.1 ACVRLK1, ORW2, HHT2, ALK1, HHT activin A receptor type II-like 1 (ACVRL1) ADCK1 NM_020421.2 FLJ39600 aarF domain containing kinase 1 (ADCK1) ADCK2 NM_052853.3 MGC20727 aarF domain containing kinase 2 (ADCK2) ADCK3 NM_020247.3 CABC1, COQ8, SCAR9 chaperone, ABC1 activity of bc1 complex like (S. pombe) (CABC1) ADCK4 NM_024876.3 aarF domain containing kinase 4 (ADCK4) ADCK5 NM_174922.3 FLJ35454 aarF domain containing kinase 5 (ADCK5) ADRBK1 NM_001619.2 GRK2, BARK1 adrenergic, beta, receptor kinase 1 (ADRBK1) ADRBK2 NM_005160.2 GRK3, BARK2 adrenergic, beta, receptor kinase 2 (ADRBK2) AKT1 NM_001014431.1 RAC, PKB, PRKBA, AKT v-akt murine thymoma viral oncogene homolog 1 (AKT1) AKT2 NM_001626.2 v-akt murine thymoma viral oncogene homolog 2 (AKT2) AKT3 NM_181690.1
    [Show full text]
  • Sensitivity and Gene Expression Profile of Fresh Human Acute
    Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868 Lars Petter Jordheim, Adriana Plesa, Michel Dreano, Emeline Cros-Perrial, Céline Keime, Stéphanie Herveau, Delphine Demangel, Julie A. Vendrell, Charles Dumontet To cite this version: Lars Petter Jordheim, Adriana Plesa, Michel Dreano, Emeline Cros-Perrial, Céline Keime, et al.. Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed exvivo to AS602868. Cancer Chemotherapy and Pharmacology, Springer Verlag, 2010, 68 (1), pp.97-105. 10.1007/s00280-010-1458-y. hal-00624174 HAL Id: hal-00624174 https://hal.archives-ouvertes.fr/hal-00624174 Submitted on 16 Sep 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Sensitivity and Gene Expression Profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868 Running title: Gene expression profile of AS602868 Lars Petter Jordheim1,2,3, Adriana Plesa4, Michel Dreano5, Emeline Cros-Perrial1,2, Céline Keime3,6, Stéphanie Herveau1,2, Delphine Demangel3,
    [Show full text]
  • Comprehensive Analysis of Genes Involved in the Malignancy of Gastrointestinal Stromal Tumors
    ANTICANCER RESEARCH 30: 2705-2712 (2010) Comprehensive Analysis of Genes Involved in the Malignancy of Gastrointestinal Stromal Tumors MIYAKO TSUMURAYA1, HIROYUKI KATO1, KAZUHITO MIYACHI1, KINRO SASAKI1, MASAHIRO TSUBAKI1, KAZUMI AKIMOTO2 and MASAKATSU SUNAGAWA1 1Department of Surgical Oncology (Surgery I), and 2General Medical Institution, Dokkyo Medical University, Tochigi 321-0293, Japan Abstract. Background: During tumorigenesis of gastro- Gastrointestinal stromal tumors (GISTs) are mesenchymal intestinal stromal tumors (GISTs), the most frequent changes tumors that arise in the gastrointestinal tract, and account for are reported to be gain-of-function mutations in the C-KIT about 1% of gastrointestinal tumors (1). During tumorigenesis proto-oncogene. However, we speculated that additional of GISTs, the most frequent changes are reported to be gain- genetic alterations are required for the progression of GISTs. of-function mutations in the C-KIT proto-oncogene. These Patients and Methods: Using 15 cases diagnosed with GISTs, mutations can result in autophosphorylation, namely KIT we searched for novel indicator genes by microarray ligand-independent kinase activity (2). Approximately 95% analyses using an Oligo GEArray® PI3K-AKT Signaling of GISTs express the receptor tyrosine kinase KIT, which is Pathway Microarray Kit. In addition, we analyzed the useful for distinguishing these tumors from other sarcomas mutational status of C-KIT and the proliferation status that develop in the abdomen (3). In recent years, it has been indicated by the Ki-67 index. Results: The tumor established that 75-80% of GISTs harbor mutations in the localizations of the 15 GISTs were as follows: 8 in the KIT gene, and that the resulting KIT mutants play important stomach; 2 in the small intestine; 2 in the mesentery; 1 in roles in the development of these tumors (3).
    [Show full text]
  • Identifying Factors That Conctribute to Phenotypic Heterogeneity in Melanoma Progression
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 Identifying factors that conctribute to Phenotypic heterogeneity in melanoma progression Widmer, Daniel Simon Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-73667 Dissertation Originally published at: Widmer, Daniel Simon. Identifying factors that conctribute to Phenotypic heterogeneity in melanoma progression. 2012, University of Zurich, Faculty of Medicine. Eidgenössische Technische Hochschule Zürich Swiss Federal Institute of Technology Zurich Identifying factors that conctribute to Phenotypic heterogeneity in melanoma progression Daniel Simon Widmer 2012 Diss ETH No. 20537 DISS. ETH NO. 20537 IDENTIFYING FACTORS THAT CONTRIBUTE TO PHENOTYPIC HETEROGENEITY IN MELANOMA PROGRESSION A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by Daniel Simon Widmer Master of Science UZH University of Zurich born on February 26th 1982 citizen of Gränichen AG accepted on the recommendation of Professor Sabine Werner, examinor Professor Reinhard Dummer, co-examinor Professor Michael Detmar, co-examinor 2012 Contents 1. ZUSAMMENFASSUNG...................................................................................................... 7 2. SUMMARY ................................................................................................................... 11 3. INTRODUCTION ...........................................................................................................
    [Show full text]
  • Genetic Variants of the Protein Kinase C-Β 1 Gene and Development Of
    Supplementary Online Content Ma RCW, Tam CHT, Wang Y, et al. Genetic variants of the protein kinase C-β 1 gene and development of end-stage renal disease in patients with type 2 diabetes. JAMA. 2010;304(8):881-889. eFigure. Structure of PRKCB1 gene and the location of SNPs genotyped eTable 1. Clinical characteristics and biochemical profile at baseline and allele frequencies at each polymorphic site of PRKCB1 stratified according to the progression to ESRD and CKD for the replication stage in Chinese type 2 diabetic patients eTable 2. Genotype distributions of PRKCB1 SNPs and hazard ratio of PRKCB1 polymorphisms for risk of CKD for the validation study in young onset Chinese type 2 diabetic patients eTable 3. Clinical characteristics of type 2 diabetic patients from the Shanghai cohort eTable 4. Functional annotation of the implicated genetic variants in PRKCB1 This supplementary material has been provided by the authors to give readers additional information about their work. © 2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 eFigure. Structure of PRKCB1 gene and the location of SNPs genotyped. Shades of grey (white, shades of grey and black colour refer to r2 = 0, 0 < r2 < 1 and r2 = 1, respectively) and red (bright red and white refer to high and low |D’|, respectively) indicate the strength of pairwise LDs based on r2 and |D’| respectively. “†”refer to SNP show significant association to ESRD endpoint in the present study. † † † † © 2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 eTable 1.
    [Show full text]
  • Supplemental Tables
    JPET #237347 (suppl) Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ Rodger A Allen, Daniel C Brookings, Mark J Powell1,2, Jean Delgado, Lindsay K Shuttleworth, Mark Merriman, Ian J Fahy1,3, Roohi Tewari, John P Silva, Louise J Healy1,4, Gareth C G Davies, Breda Twomey, Rona M Cutler, Apoorva Kotian, Andrea Crosby, Gillian McCluskey, Gillian F Watt and Andrew Payne The Journal of Pharmacology and Experimental Therapeutics Supplementary Table 1. Human primary cell systems in BioMap profile System Primary human cell systems Stimulation 3C Venular endothelial cells IL-1β, TNFα and IFNγ 4H Venular endothelial cells IL-4 and histamine LPS PBMCs + venular endothelial cells TLR4 ligand SAg PBMCs + venular endothelial cells TCR ligands (1x) BE3C Bronchial epithelial cells α-IgM and TCR ligands (0.001x) CASM3C Coronary artery smooth muscle cells IL-1β, TNFα and IFNγ HDF3CGF Dermal fibroblasts IL-1β, TNFα and IFNγ IL-1β, TNFα, IFNγ, EGF, bFGF and MyoF Lung fibroblasts PDGF-BB Venular endothelial cells + M1 TNFα and TGFβ /Mphg macrophages BT B cells + PBMCs Zymosan (TLR2 ligand) 1 JPET #237347 (suppl) Supplementary Table 2A. Off-target activity: Seletalisib at a concentration of 10 µM was assessed in binding or activity assays against a panel of 239 kinase enzymes Seletalisib % inhibition of control Kinase values CAMK1 (CaMK1) -15 CDK7/cyclin H/MNAT1 17 CDK9/cyclin T1 -24 CHUK (IKK alpha) -4 DAPK1 -13 GSG2 (Haspin) -12 IRAK1 0 LRRK2 -18 NUAK1 (ARK5) -18 PI4KA (PI4K alpha) -21 PI4KB (PI4K beta) -20 PIK3C2A (PI3K-C2
    [Show full text]
  • Identification of New Kinase Clusters Required for Neurite Outgrowth And
    Cell Death and Differentiation (2008) 15, 283–298 & 2008 Nature Publishing Group All rights reserved 1350-9047/08 $30.00 www.nature.com/cdd Identification of new kinase clusters required for neurite outgrowth and retraction by a loss-of-function RNA interference screen SHY Loh1, L Francescut1, P Lingor2,3,MBa¨hr2,3 and P Nicotera*,1 Disruption of synaptic integrity, loss of connectivity and axodendritic degeneration are early and essential components of neurodegeneration. Although neuronal cell death mechanisms have been thoroughly investigated, less is known about the signals involved in axodendritic damage and the processes involved in regeneration. Here we conducted a genome-wide RNA interference-based forward genetic screen, using small interfering RNA targeting all human kinases, and identified clusters of kinases families essential for growth cone collapse, neurite retraction and neurite outgrowth. Of 59 kinases identified as positive regulators of neurite outgrowth, almost 50% were in the tyrosine kinase/tyrosine kinase-like (TK/TKL) receptor subgroups, underlining the importance of extracellular ligands in this process. Neurite outgrowth was inhibited by 66 other kinases, none of which were TK/TKL members, whereas 79 kinases inhibited lysophosphatidic acid-induced neurite retraction. Twenty kinases were involved in both inhibitory processes suggesting shared mechanisms. Within this group of 20 kinases, some (ULK1, PDK1, MAP4K4) have been implicated previously in axonal events, but others (MAST2, FASTK, CKM and DGUOK) have not. For a subset of kinases, the effect on neurite outgrowth was validated in rat primary cerebellar cultures. The ability to affect regeneration was further tested in a model of axodendritic lesion using primary rat midbrain cultures.
    [Show full text]