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Supplementary Figure S1. Determination of the binding mode of the FGFR inhibitor CH5183284/Debio 1347. Lineweaver-Burk plot of FGFR1 with different concentrations.

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Presentation on theme: "Supplementary Figure S1. Determination of the binding mode of the FGFR inhibitor CH5183284/Debio 1347. Lineweaver-Burk plot of FGFR1 with different concentrations."— Presentation transcript:

1 Supplementary Figure S1. Determination of the binding mode of the FGFR inhibitor CH /Debio Lineweaver-Burk plot of FGFR1 with different concentrations of ATP in presence of various concentrations of CH /Debio Linear graphs intersected all with y-axis (i.e. V max unchanged) which does support an ATP-competitive mode-of-action of CH /Debio 1347 for FGFR1. Supplementary Figure S1.

2 Supplementary Figure S2. Effects of CH /Debio 1347 and cediranib on in vitro VEGF-induced tube formation (A) Inhibition of tube formation by CH /Debio 1347 and cediranib in a HUVEC and fibroblast co-culture system. Total vessel area was measured quantitatively for the area of capillary-like tube formation with Kurabo angiogenesis image analysis software. N=3. (B) Representative mages of tube formation of HUVEC. x4 objective. (a) DMSO treatment. (b) 0.1 µM of CH /Debio (c) 1 µM of CH /Debio (d) 0.01 µM of cediranib. (e) 0.1 µM of cediranib. A. (a) (b) (c) (d) (e) B. Supplementary Figure S2.

3 Supplementary Figure S3. Kinase activity of FGFR2 WT, V564F, V564I, and V564L mutants. The 293 cells were transiently transfected with pCXND3 FGFR2 WT, FGFR2 V564F, FGFR2 V564I, and FGFR2 V564L. The kinases were immunoprecipitated with anti-FGFR2 antibody. Then, kinase activity was evaluated by examining their ability to phosphorylate substrate peptide using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. (N=2) Relative kinase activity of FGFR2 to mock Supplementary Figure S3.

4 Supplementary Figure S4. Inhibition of cellular pY-FGFR2 WT, pY-FGFR2 V564F, pY- FGFR2 V564I, and pY-FGFR2 V564L. The HCT-116 cells were transiently transfected with pCXND3 FGFR2 WT, FGFR2 V564F, FGFR2 V564I, and FGFR2 V564L. A day after the transfection, the cells were treated with the indicated concentration of CH /Debio 1347 or AZD4547 for 2 h. Cells were extracted and analyzed by Western blotting. WT V564F 0 V564L AZD4547 V564I CH (µM) AZD4547CH pY-FGFRFGFR2 Supplementary Figure S4.

5 pY-FGFR WT CH AZD4547 NVP-BGJ398 DMSO TEL-FGFR2 V564F CH AZD4547 NVP-BGJ398 DMSO Supplementary Figure S5. Susceptibility of CH /Debio 1347 against gatekeeper mutants of FGFR2. (A) Anti-proliferative activity of PD and cediranib against TEL-FGFR2 WT driven Ba/F3 cells and TEL-FGFR2 V564F-driven Ba/F3 cells. Three clones were treated with various concentrations of the indicated inhibitors for 4 days. The viable cells were counted with WST-8. (B) TEL-FGFR2 WT driven Ba/F3 and TEL-FGFR2 V564-driven Ba/F3 were treated with the indicated 1 μM of CH /Debio 1347, AZD4547, and NVP-BGJ398 for 2 hours. Cells were extracted and analyzed by Western blotting. A. % inhibition Drug conc. μM ( log 10 ) B. PD173074cediranib Supplementary Figure S5.

6 Actin TEL-FGFR2 WT pY-FGFR Vehicle CH (mg/kg) AZD4547 (mg/kg) Supplementary Figure S6. Antitumor activity of CH /Debio 1347 and AZD4547 in Ba/F3 TEL-FGFR2 WT-driven mouse model. (A) Mice bearing Ba/F3 TEL-FGFR2 WT cells were treated with CH /Debio 1347 or AZD4547 orally once daily for 11 days at the indicated doses. Tumor volume and body weight change for each dose group were measured. Data are shown as mean ± SD (n = 5). (B) Suppression of phospho-FGFR inhibition in xenograft tissue. Mice bearing Ba/F3 TEL- FGFR2 WT cells were treated for 11 days at 50 and 100 mg/kg of CH /Debio 1347 or 25 and 50 mg/kg of AZD4547, and xenograft tumors were extracted at 4 hours post- dosing and analyzed by Western blotting. (n = 3) Tumor volume (mm3) Days after the inoculation A. CH AZD4547 B. Supplementary Figure S6.

7 Supplementary Figure S7. Kinase inhibition assay of FGFR2 WT or FGFR2 N549H mutant Kinase inhibitory activity of FGFR inhibitors against FGFR2 WT or FGFR2 N549H were measured (n=3). CH , dovitinib, AZD4547, NVP-BGJ398, and PD showed 12, 5.2, 26, 19, 30 fold higher IC 50 against FGFR2 N549H than FGFR2 WT, respectively. CH AZD4547NVP-BGJ398PD dovitinib % inhibition Drug conc. μM ( log 10 ) % inhibition Drug conc. μM ( log 10 ) % inhibition Drug conc. μM ( log 10 ) % inhibition Drug conc. μM ( log 10 ) WT N549H Supplementary Figure S7.

8 Supplementary Table S1 Crystallographic data collection and refinement statistics for FGFR1 in complex with CH /Debio Data collection X-ray sourcePXII/X10SA (SLS) Wavelength [Å]1.000 DetectorPILATUS 6M Temperature [K]100 Resolution [Å] Observed reflections Unique reflections Completeness [%] R sym [%] R meas [%] I/sigma(I) Space groupC Unit cell (a, b, c) [Å]211.21, 56.75, 65.45, 90, , 90 Refinement Resolution Number of reflections (working/test) / 1954 R cryst [%]22.3 R free [%]25.7 Number of atoms: Protein4460 Ligand54 Water75 Phosphate ion5 Deviation from ideal geometry: Bond lengths [Å]0.010 Bond angles [ °]1.03 Ramachandran plot: Most favoured regions92.2 Additional allowed regions7.0 Generously allowed regions0.8 Supplementary Table S1.

9 Supplementary Table S2 Kinase selectivity profile of CH /Debio The values of % competition at 0.1 or 1 μM CH /Debio 1347 in DiscoveRx’s KINOMEscan for 442 kinases including mutated kinases. Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan AAK1<65 ABL1(E255K)-phosphorylated<65 ABL1(F317I)-nonphosphorylated<65 ABL1(F317I)-phosphorylated<65 ABL1(F317L)-nonphosphorylated<65 ABL1(F317L)-phosphorylated<65 ABL1(H396P)-nonphosphorylated<6574 ABL1(H396P)-phosphorylated<65 ABL1(M351T)-phosphorylated<65 ABL1(Q252H)-nonphosphorylated<6565 ABL1(Q252H)-phosphorylated<65 ABL1(T315I)-nonphosphorylated<65 ABL1(T315I)-phosphorylated<65 ABL1(Y253F)-phosphorylated<65 ABL1-nonphosphorylated<65 ABL1-phosphorylated<65 ABL2<65 ACVR1<65 ACVR1B<65 ACVR2A<65 ACVR2B<6572 ACVRL1<65 ADCK3<65 ADCK4<65 AKT1<65 AKT2<65 AKT3<65 ALK<65 AMPK-alpha1<65 AMPK-alpha2<65 ANKK1<65 ARK5<65 ASK1<65 ASK2<65 AURKA<65 AURKB<65 AURKC<65 AXL<65 BIKE<65 BLK<6585 BMPR1A<65 BMPR1B<65 BMPR2<65 BMX<65 BRAF<65 BRAF(V600E)<65 BRK<65 BRSK1<65 BRSK2<65 Supplementary Table S2.

10 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan BTK<65 CAMK1<65 CAMK1D<65 CAMK1G<65 CAMK2A<65 CAMK2B<65 CAMK2D<65 CAMK2G<65 CAMK4<65 CAMKK1<65 CAMKK2<65 CASK<65 CDC2L1<65 CDC2L2<65 CDC2L5<65 CDK11<65 CDK2<65 CDK3<65 CDK4-cyclinD1<65 CDK4-cyclinD3<65 CDK5<65 CDK7<65 CDK8<65 CDK9<65 CDKL1<65 CDKL2<65 CDKL3<65 CDKL5<65 CHEK1<65 CHEK2<65 CIT<65 CLK1<65 CLK2<65 CLK3<65 CLK4<65 CSF1R7699 CSK<65 CSNK1A1<65 CSNK1A1L<65 CSNK1D<65 CSNK1E<65 CSNK1G1<65 CSNK1G2<65 CSNK1G3<65 CSNK2A1<65 CSNK2A2<65 CTK<65 DAPK1<65 DAPK2<65 Supplementary Table S2 (cont).

11 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan DAPK3<65 DCAMKL1<65 DCAMKL2<65 DCAMKL3<65 DDR1<6572 DDR2<65 DLK<65 DMPK<65 DMPK2<65 DRAK1<65 DRAK2<65 DYRK1A<65 DYRK1B<65 DYRK2<65 EGFR<65 EGFR(E746-A750del)<65 EGFR(G719C)<65 EGFR(G719S)<65 EGFR(L747-E749del, A750P)<65 EGFR(L747-S752del, P753S)<65 EGFR(L747-T751del,Sins)<65 EGFR(L858R)<65 EGFR(L858R,T790M)<65 EGFR(L861Q)<65 EGFR(S752-I759del)<65 EGFR(T790M)<65 EIF2AK1<65 EPHA1<65 EPHA2<65 EPHA3<65 EPHA4<65 EPHA5<65 EPHA6<65 EPHA7<65 EPHA8<65 EPHB1<65 EPHB2<65 EPHB3<65 EPHB4<65 EPHB6<6592 ERBB2<65 ERBB3<65 ERBB4<65 ERK1<65 ERK2<65 ERK3<65 ERK4<65 ERK5<65 ERK8<65 Supplementary Table S2 (cont).

12 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan ERN1<65 FAK<65 FER<65 FES<65 FGFR FGFR28797 FGFR38099 FGFR3(G697C)8599 FGFR4<65 FGR<6582 FLT1<65 FLT3<65 FLT3(D835H)<65 FLT3(D835Y)<65 FLT3(ITD)<65 FLT3(K663Q)<65 FLT3(N841I)<65 FLT3(R834Q)<65 FLT4<65 FRK<65 FYN<65 GAK<65 GCN2(Kin.Dom.2,S808G)<65 GRK1<65 GRK4<65 GRK7<65 GSK3A<65 GSK3B<65 HCK<65 HIPK1<65 HIPK2<65 HIPK3<65 HIPK4<65 HPK1<65 HUNK<65 ICK<65 IGF1R<65 IKK-alpha<65 IKK-beta<65 IKK-epsilon<65 INSR<65 INSRR<65 IRAK1<65 IRAK3<65 IRAK4<65 ITK<65 JAK1(JH1domain-catalytic)<65 JAK1(JH2domain-pseudokinase)<65 JAK2(JH1domain-catalytic)<65 Supplementary Table S2 (cont).

13 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan JAK3(JH1domain-catalytic)<65 JNK1<65 JNK2<65 JNK3<65 KIT92100 KIT(A829P)<65 KIT(D816H)<65 KIT(D816V)<65 KIT(L576P)8799 KIT(V559D)95100 KIT(V559D,T670I)<65 KIT(V559D,V654A)<6583 LATS1<65 LATS2<65 LCK<65 LIMK1<65 LIMK2<65 LKB1<65 LOK<65 LRRK2<65 LRRK2(G2019S)<65 LTK<65 LYN<6565 LZK<65 MAK<65 MAP3K1<65 MAP3K15<65 MAP3K2<65 MAP3K3<65 MAP3K4<65 MAP4K2<65 MAP4K3<65 MAP4K4<65 MAP4K5<65 MAPKAPK2<65 MAPKAPK5<65 MARK1<65 MARK2<65 MARK3<65 MARK4<65 MAST1<65 MEK1<65 MEK2<65 MEK3<65 MEK4<65 MEK5<6570 MEK6<65 MELK<65 MERTK<65 Supplementary Table S2 (cont).

14 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan MET<65 MET(M1250T)<65 MET(Y1235D)<65 MINK<65 MKK7<65 MKNK1<65 MKNK2<65 MLCK<65 MLK1<65 MLK2<65 MLK3<65 MRCKA<65 MRCKB<65 MST1<65 MST1R<65 MST2<65 MST3<65 MST4<65 MTOR<65 MUSK<65 MYLK<65 MYLK2<65 MYLK4<65 MYO3A<65 MYO3B<65 NDR1<65 NDR2<65 NEK1<65 NEK11<65 NEK2<65 NEK3<65 NEK4<65 NEK5<65 NEK6<65 NEK7<65 NEK9<65 NIM1<65 NLK<65 OSR1<65 p38-alpha<65 p38-beta<65 p38-delta<65 p38-gamma<65 PAK1<65 PAK2<65 PAK3<65 PAK4<65 PAK6<65 PAK7<65 Supplementary Table S2 (cont).

15 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan PCTK1<65 PCTK2<65 PCTK3<65 PDGFRA7699 PDGFRB92100 PDPK1<65 PFCDPK1(P.falciparum)<65 PFPK5(P.falciparum)<65 PFTAIRE2<65 PFTK1<65 PHKG1<65 PHKG2<65 PIK3C2B<65 PIK3C2G<65 PIK3CA<65 PIK3CA(C420R)<65 PIK3CA(E542K)<65 PIK3CA(E545A)<65 PIK3CA(E545K)<65 PIK3CA(H1047L)<65 PIK3CA(H1047Y)<65 PIK3CA(I800L)<65 PIK3CA(M1043I)<65 PIK3CA(Q546K)<65 PIK3CB<65 PIK3CD<65 PIK3CG<65 PIK4CB<65 PIM1<65 PIM2<65 PIM3<65 PIP5K1A<65 PIP5K1C<65 PIP5K2B<65 PIP5K2C<65 PKAC-alpha<65 PKAC-beta<65 PKMYT1<65 PKN1<65 PKN2<65 PKNB(M.tuberculosis)<65 PLK1<65 PLK2<65 PLK3<65 PLK4<65 PRKCD<65 PRKCE<65 PRKCH<65 PRKCI<65 Supplementary Table S2 (cont).

16 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan PRKCQ<65 PRKD1<65 PRKD2<65 PRKD3<65 PRKG1<65 PRKG2<65 PRKR<65 PRKX<65 PRP4<65 PYK2<65 QSK<65 RAF1<65 RET<6591 RET(M918T)<6594 RET(V804L)<65 RET(V804M)<65 RIOK1<65 RIOK2<65 RIOK3<65 RIPK1<65 RIPK2<65 RIPK4<65 RIPK5<65 ROCK1<65 ROCK2<65 ROS1<65 RPS6KA4(Kin.Dom.1-N-terminal)<65 RPS6KA4(Kin.Dom.2-C-terminal)<65 RPS6KA5(Kin.Dom.1-N-terminal)<65 RPS6KA5(Kin.Dom.2-C-terminal)<65 RSK1(Kin.Dom.1-N-terminal)<65 RSK1(Kin.Dom.2-C-terminal)<65 RSK2(Kin.Dom.1-N-terminal)<65 RSK3(Kin.Dom.1-N-terminal)<65 RSK3(Kin.Dom.2-C-terminal)<65 RSK4(Kin.Dom.1-N-terminal)<65 RSK4(Kin.Dom.2-C-terminal)<65 S6K1<65 SBK1<65 SgK110<65 SGK3<65 SIK<65 SIK2<65 SLK<65 SNARK<65 SNRK<65 SRC<65 SRMS<65 SRPK1<65 Supplementary Table S2 (cont).

17 Kinase % competition at 100 nM in KINOMEscan % competition at 1000 nM in KINOMEscan SRPK2<65 SRPK3<65 STK16<65 STK33<65 STK35<65 STK36<65 STK39<65 SYK<65 TAK1<65 TAOK1<65 TAOK2<65 TAOK3<65 TBK1<65 TEC<65 TESK1<65 TGFBR1<65 TGFBR2<65 TIE1<65 TIE2<65 TLK1<65 TLK2<65 TNIK<65 TNK1<65 TNK2<65 TNNI3K<65 TRKA<65 TRKB<65 TRKC<65 TRPM6<65 TSSK1B<65 TTK<65 TXK<65 TYK2(JH1domain-catalytic)<65 TYK2(JH2domain-pseudokinase)<65 TYRO3<65 ULK1<65 ULK2<65 ULK3<65 VEGFR2<65 VRK2<65 WEE1<65 WEE2<65 YANK1<65 YANK2<65 YANK3<65 YES<65 YSK1<65 YSK4<65 ZAK<65 ZAP70<65 Supplementary Table S2 (cont).

18 Supplementary Table S3 Selective antiproliferative activity of CH /Debio 1347 against cancer cell lines harboring genetic alterations in FGFR Cell lineTumor type CH IC50 (µM) FGFR genetic alterations SNU-16Gastric cancer0.017FGFR2 gene amplification Kato-IIIGastric cancer0.018FGFR2 gene amplification HSC-39Gastric cancer0.050FGFR2 gene amplification AGSGastric cancer2.9 HGC-27Gastric cancer3.0 MKN-1Gastric cancer3.0 MKN-45Gastric cancer5.0 SNU-1Gastric cancer5.0 JR-StGastric cancer7.1 NCI-N87Gastric cancer10 NUGC-4Gastric cancer>10 MKN-74Gastric cancer>10 NUGC-3Gastric cancer>10 SCHGastric cancer>10 MKN-28Gastric cancer>10 SNU-5Gastric cancer>10 MFE-296Endometrial cancer0.042FGFR2 N549K mutation AN3 CAEndometrial cancer0.054FGFR2 K310R/N549K mutation MFE-280Endometrial cancer0.41FGFR2 S252W mutation HEC-59Endometrial cancer2.8 HEC-1-BEndometrial cancer5.7 HEC-1-AEndometrial cancer9.2 KLEEndometrial cancer10 HEC-151Endometrial cancer10 RL95-2Endometrial cancer>10 HEC-50BEndometrial cancer>10 HEC-108Endometrial cancer>10 RT112/84Bladder cancer0.018FGFR3-TACC3 fusion UM-UC-14Bladder cancer0.11FGFR3 S249C mutation SW780Bladder cancer0.12FGFR3-BAIAP2L1 fusion RT4Bladder cancer0.35FGFR3-TACC3 fusion T24Bladder cancer Bladder cancer3.5 J82Bladder cancer4.1 SCaBERBladder cancer5.8 JMSU1Bladder cancer7.1 UM-UC-3Bladder cancer7.2 HT-1376Bladder cancer10 HT-1197Bladder cancer>10 TCCSUPBladder cancer>10 BFTC-905Bladder cancer> VBladder cancer>10 KMS-11Multiple Myeloma0.14FGFR3 Y373C mutation OPM-2Multiple Myeloma1.3 KMS-12-PEMultiple Myeloma2.7 KMS-26Multiple Myeloma3.0 KMS-21BMMultiple Myeloma4.5FGFR3 K650E mutation NCI-H929Multiple Myeloma5.6 IM-9Multiple Myeloma6.0FGFR3 F386L mutation KMS-34Multiple Myeloma7.7 Supplementary Table S3.

19 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations KMM-1Multiple Myeloma8.6 KMS-12-BMMultiple Myeloma>10 KHM-1BMultiple Myeloma>10 LP-1Multiple Myeloma>10 KMS-20Multiple Myeloma>10 L-363Multiple Myeloma>10 KMS-28BMMultiple Myeloma>10 NCI-H520Non-small cell lung cancer, Squamouse0.30FGFR1 gene amplification PC-1Non-small cell lung cancer, Squamouse1.3 HARANon-small cell lung cancer, Squamouse9.1 HARA-BNon-small cell lung cancer, Squamouse9.8 NCI-H226Non-small cell lung cancer, Squamouse>10 QG-56Non-small cell lung cancer, Squamouse>10 NCI-H2170Non-small cell lung cancer, Squamouse>10 Calu-1Non-small cell lung cancer, Squamouse>10 PC-10Non-small cell lung cancer, Squamouse>10FGFR2 V12M mutation SK-MES-1Non-small cell lung cancer, Squamouse>10 NCI-H1703Non-small cell lung cancer, Adenocarcinoma0.79FGFR1 gene amplification PC-9Non-small cell lung cancer, Adenocarcinoma2.8 HCC78Non-small cell lung cancer, Adenocarcinoma5.0 ABC-1Non-small cell lung cancer, Adenocarcinoma5.5 NCI-H1395Non-small cell lung cancer, Adenocarcinoma5.9 NCI-H23Non-small cell lung cancer, Adenocarcinoma6.0 NCI-H2009Non-small cell lung cancer, Adenocarcinoma6.8 NCI-H1755Non-small cell lung cancer, Adenocarcinoma8.0 NCI-H1568Non-small cell lung cancer, Adenocarcinoma9.2 NCI-H2122Non-small cell lung cancer, Adenocarcinoma>10 NCI-H838Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1355Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1944Non-small cell lung cancer, Adenocarcinoma>10 COR-L105Non-small cell lung cancer, Adenocarcinoma>10 SK-LU-1Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1437Non-small cell lung cancer, Adenocarcinoma>10 HCC827Non-small cell lung cancer, Adenocarcinoma>10 NCI-H2347Non-small cell lung cancer, Adenocarcinoma>10 NCI-H522Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1993Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1792Non-small cell lung cancer, Adenocarcinoma>10 A549Non-small cell lung cancer, Adenocarcinoma>10 NCI-H2023Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1975Non-small cell lung cancer, Adenocarcinoma>10 NCI-H2228Non-small cell lung cancer, Adenocarcinoma>10 Calu-3Non-small cell lung cancer, Adenocarcinoma>10 NCI-H2030Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1838Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1793Non-small cell lung cancer, Adenocarcinoma>10 NCI-H1581Non-small cell lung cancer, Large cell0.22FGFR1 gene amplification NCI-H292Non-small cell lung cancer, Mucoepidermoid1.9 NCI-H1155Non-small cell lung cancer, Large cell2.1 NCI-H1666Non-small cell lung cancer, Bronchiolo-Alveolar5.3 Supplementary Table S3 (cont).

20 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations NCI-H596Non-small cell lung cancer, Adenosquamous6.1 NCI-H2110Non-small cell lung cancer6.9 Calu-6Non-small cell lung cancer8.2 NCI-H661Non-small cell lung cancer, Large cell8.6 NCI-H460Non-small cell lung cancer, Large cell8.9 NCI-H441Non-small cell lung cancer, Papillary>10 HCC366Non-small cell lung cancer, Adenosquamous>10 PC-13Non-small cell lung cancer, Large cell>10 NCI-H1299Non-small cell lung cancer, Large cell>10 NCI-H1650Non-small cell lung cancer, Bronchiolo-Alveolar>10 NCI-H1781Non-small cell lung cancer, Bronchiolo-Alveolar>10 LCLC-103HNon-small cell lung cancer, Large cell>10 DMS 114Small cell lung cancer0.18FGFR1 gene amplification NCI-H2227Small cell lung cancer1.4 NCI-H82Small cell lung cancer2.6 SHP-77Small cell lung cancer5.6 NCI-H526Small cell lung cancer8.7 NCI-H1930Small cell lung cancer>10 DMS 53Small cell lung cancer>10 SUM-52PEBreast cancer0.018FGFR2 gene amplification MFM-223Breast cancer0.058FGFR2 gene amplification HCC2218Breast cancer1.2 MCF10DCIS.comBreast cancer1.6 MDA-MB-157Breast cancer2.3 DU-4475Breast cancer3.1 Hs 578.TBreast cancer3.7 MCF10ABreast normal6.2 HCC38Breast cancer6.4 SUM-44PEBreast cancer6.9FGFR1 gene amplification SUM-229PEBreast cancer7.4 MDA-MB-453Breast cancer7.7 MDA-MB-468Breast cancer8.0 MCF7Breast cancer8.4 HCC1500Breast cancer8.6 HCC1187Breast cancer9.2 MDA-MB-175-VIIBreast cancer>10 CAL-120Breast cancer>10FGFR1 gene amplification HCC1569Breast cancer>10 HCC1599Breast cancer>10 ZR-75-1Breast cancer>10FGFR1 gene amplification MDA-MB-231Breast cancer>10 JIMT-1Breast cancer>10FGFR1 gene amplification CAMA-1Breast cancer>10FGFR1 gene amplification HCC1395Breast cancer>10FGFR1 S125L mutation BT-474Breast cancer>10 HCC1806Breast cancer>10 HCC70Breast cancer>10 HCC1954Breast cancer>10 T47DBreast cancer>10 HCC1419Breast cancer>10 Supplementary Table S3 (cont).

21 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations ZR-75-30Breast cancer>10 HCC1937Breast cancer>10 SK-BR-3Breast cancer>10 HCC1428Breast cancer>10 COLO-824Breast cancer>10 UACC-812Breast cancer>10 HCC1143Breast cancer>10 MDA-MB-361Breast cancer>10 BT-20Breast cancer>10 MDA-MB-134-VIBreast cancer>10FGFR1 gene amplification BT-483Breast cancer>10 NCI-H716Colorectal cancer0.013FGFR2 gene amplification COLO-205Colorectal cancer2.9 HCT-8Colorectal cancer3.2 CaR-1Colorectal cancer5.8 SW48Colorectal cancer5.9 LS174TColorectal cancer7.5 LS513Colorectal cancer7.9 HT-29Colorectal cancer7.9 COLO-201Colorectal cancer7.9 NCI-H508Colorectal cancer8.3 SW620Colorectal cancer8.3 RKOColorectal cancer8.7 SW480Colorectal cancer8.8 LS411NColorectal cancer9.0 HCT-116Colorectal cancer10 LS1034Colorectal cancer>10 HCT-15Colorectal cancer>10 WiDrColorectal cancer>10 CW-2Colorectal cancer>10 T84Colorectal cancer>10 SW948Colorectal cancer>10 SW1417Colorectal cancer>10 DLD-1Colorectal cancer>10 SW1463Colorectal cancer>10 LoVoColorectal cancer>10 SW403Colorectal cancer>10 Caco-2Colorectal cancer>10 COLO-320DMColorectal cancer>10 SW1116Colorectal cancer>10 KG-1Leukemia, Myeloid, Acute0.014FGFR1OP-FGFR1 fusion KG-1aLeukemia, Myeloid, Acute0.030FGFR1OP-FGFR1 fusion MV-4-11Leukemia, Biphenotypic, Acute1.9 NB-4Leukemia, Promyelocytic, Acute2.1 10C9Lymphoma, Non-Hodgkin2.3 MOLM-13Leukemia, Myeloid, Acute2.5 RajiBurkitt Lymphoma3.1 RamosBurkitt Lymphoma3.5 MEG-01Leukemia, Myelogenous, Chronic4.1 MC/CARPlasmacytoma4.1 Supplementary Table S3 (cont).

22 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations KARPAS-299Lymphoma, Large-Cell, Anaplastic4.1 U-698-MLymphoma, B-Cell4.4 K-562Leukemia, Myelogenous, Chronic5.0 CMK-11-5Leukemia, Megakaryoblastic, Acute5.1 ARH-77Leukemia5.6 NKM-1Leukemia, Myeloid, Acute5.7 U-937Lymphoma, Large B-Cell, Diffuse6.1 SRLymphoma, Large-Cell, Immunoblastic6.2 SU-DHL-1Lymphoma, Large-Cell, Anaplastic>10 HELLeukemia, Erythroblastic, Acute>10 U266B1Plasmacytoma>10 CEM/C2Leukemia, T-Cell>10 TF-1aLeukemia, Erythroblastic, Acute>10 CCRF-CEMLeukemia>10 RPMI-8226Plasmacytoma>10 NOMO-1Leukemia, Myeloid, Acute>10 HL-60Leukemia, Promyelocytic, Acute>10 HDLM-2Lymph Nodes>10 F-36PLeukemia, Myeloid, Acute>10 THP-1Leukemia, Monocytic, Acute>10 SKM-1Leukemia, Myeloid, Acute>10 HMCBMelanoma0.94 SK-MEL-5Melanoma3.0 A2058Melanoma4.1 A-375Melanoma5.4FGFR2 E636K mutation SK-MEL-30Melanoma5.5 SK-MEL-1Melanoma8.9 SK-MEL-28Melanoma>10 MDA-MB-435SMelanoma>10 MeWoMelanoma>10 A-431Skin cancer, Squamous Cell>10 SK-MEL-2Melanoma>10 C32Melanoma>10 HuH-7Liver cancer3.0 HuH-1Liver cancer5.3 HepG2Liver cancer>10 PLC/PRF/5Liver cancer>10 Hep3BLiver cancer>10 SK-HEP-1Liver cancer>10 HLELiver cancer>10 Hs 38.TOvarian cancer2.3 OVMANAOvarian cancer2.7 RMG-IOvarian cancer5.9 ES2Ovarian cancer6.2 PA-1Ovarian cancer9.5 COLO-704Ovarian cancer>10 SW626Ovarian cancer>10 SK-OV-3Ovarian cancer>10 OVCAR-3Ovarian cancer>10 MCASOvarian cancer>10 Supplementary Table S3 (cont).

23 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations EFO-21Ovarian cancer>10 HPACPancreas cancer1.4 KP-4Pancreas cancer5.5 YAPCPancreas cancer5.9 Mia PaCa-2Pancreas cancer7.7 Panc-1Pancreas cancer>10 BxPC-3Pancreas cancer>10 HuP-T4Pancreas cancer>10 SU.86.86Pancreas cancer>10 Capan-1Pancreas cancer>10 HPAF-IIPancreas cancer>10 CFPAC-1Pancreas cancer>10 Capan-2Pancreas cancer>10 AsPC-1Pancreas cancer>10 Hs 766.TPancreas cancer>10 A-172Glioblastoma0.31 NCCITTeratocarcinoma0.44 SW579Thyroid cancer0.85 U-2197Histiocytoma1.1 NTERA-2Teratocarcinoma1.1 CCF-STTG1Astrocytoma1.2 KYSE-150Esophageal cancer1.3 D-341MEDMedulloblastoma1.6 NB-1Neuroblastoma1.8 HT-1080Fibrosarcoma1.8 C-33 ACervix cancer2.0 COLO-684Uterus cancer2.0 IMR-32Neuroblastoma2.2 KYSE-70Esophageal cancer2.3 TTThyroid cancer BOsteosarcoma2.9 SK-N-DZNeuroblastoma3.7 RPMI-2650Nasal cancer3.8 SH-SY5YNeuroblastoma4.0 Ca SkiCervix cancer4.2 SJCRH30Rhabdomyosarcoma4.3 SCC-9Tongue cancer4.4 T98GGlioblastoma4.5 DaoyMedulloblastoma ORenal cancer6.0 D-283MEDMedulloblastoma6.1 OE19Esophageal cancer6.4 NCI-H358Bronchial cancer6.6 EGI-1Cholangiocarcinoma8.1 KYSE-520Esophageal cancer8.3 U-138 MGGlioblastoma9.8 SK-N-SHNeuroblastoma9.8 LN-18Glioblastoma9.9 SK-N-F1Neuroblastoma9.9 RH-30Rhabdomyosarcoma10 Supplementary Table S3 (cont).

24 Cell lineTumor type CH IC50 (µM) FGFR genetic alterations SK-ES-1Ewing sarcoma10 Detroit 562Pharynx cancer>10 CAL-27Tongue cancer>10 NCI-H28Mesothelioma>10 SK-N-ASNeuroblastoma>10 KELLYNeuroblastoma>10 HuH-28Cholangiocarcinoma>10 ACHNRenal cancer>10 Caki-1Renal cancer>10 A-204Rhabdomyosarcoma>10 ME-180Cervix cancer>10 SNG-MUterus cancer>10 SCC-25Tongue cancer>10 A-673Rhabdomyosarcoma>10 PC-3Prostate cancer>10 SCC-15Tongue cancer>10 SCC-4Tongue cancer>10 22Rv1Prostate cancer>10 U-118 MGGlioblastoma> CThyroid cancer>10 DU-145Prostate cancer>10 U-87 MGGlioblastoma>10 VCaPProstate cancer>10 MG-63Osteosarcoma>10 Y79Retinoblastoma>10 RB247cRetinoblastoma>10 WERI-Rb-1Retinoblastoma>10 Supplementary Table S3 (cont).


Download ppt "Supplementary Figure S1. Determination of the binding mode of the FGFR inhibitor CH5183284/Debio 1347. Lineweaver-Burk plot of FGFR1 with different concentrations."

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