0.1 0.1 1 10 100 1000 Measured Kd (nM) - Nature fileSupplementary Figure 1. Measured Kd (nM)...
31
Supplementary Figure 1. Measured K d (nM) Published IC 50 /K i /K d (nM) 0.1 1 10 100 1000 0.1 1 10 100 1000 Supplementary Figure 1. Comparison of K d values reported here and published biochemical IC 50 /K i /K d values for interactions between inhibitors and their primary, intended targets. Values used to create this plot are reported in Supplementary Table 3. Comparative data were available for 66 of the 72 compounds addressed in this study. The line of equivalence is indicated in solid red, and dashed red lines indicate 10-fold offsets. Nature Biotechnology: doi:10.1038/nbt.1990
Transcript of 0.1 0.1 1 10 100 1000 Measured Kd (nM) - Nature fileSupplementary Figure 1. Measured Kd (nM)...
Supplementary Figure 1.
Measured Kd (nM)
Publishe
d IC
50/K
i/Kd(nM)
0.1
1
10
100
1000
0.1 1 10 100 1000
Supplementary Figure 1. Comparison of Kd values reported here and published biochemical IC50/Ki/Kd values for interactions between inhibitors and their primary, intended targets. Values used to create this plot are reported in Supplementary Table 3. Comparative data were available for 66 of the 72 compounds addressed in this study. The line of equivalence is indicated in solid red, and dashed red lines indicate 10-fold offsets.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 2.
Supplementary Figure 2. Kinome interaction maps for the 72 compounds tested. Each red circle indicates a kinase found to bind to a compound. Larger circles indicate higher affinity interactions. Interactions with Kd < 3 µM are shown.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Figure 3.
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
a
b
Perc
ent o
f com
poun
ds
S(300 nM)
All compounds
Perc
ent o
f com
poun
ds
S(300 nM)
Type I inhibitors
c
Perc
ent o
f com
poun
ds
S(300 nM)
Type II inhibitors
Supplementary Figure 3. Quantitative distribution of kinome-wide selectivity of compounds. An alternative analysis of the data shown in Figure 1 using a cutoff of S(300 nM) instead of S(3 μM) and reduced bin sizes (0.05 units instead of 0.1). (a), (b), and (c) are otherwise as described in Figure 1.
Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
CLK2 0.51CLK4 0.53CLK1 1.4
DYRK1A 2.1DYRK1B 3.9PRKCH 9.5PRKCE 11PRKCQ 12CIT 13
A‐674563
NHN
N
O
NH2
PRKG2 19ABL1‐nonphosphorylated 2.1
CSF1R 7.6KIT 8.1
PDGFRB 8.4DDR1 8.7
PDGFRA 25DDR2 26LCK 31
ABL1‐phosphorylated 55LYN 61
AB‐1010 NHNH
O
N
S N
N
N
LYN 61FLT3 0.63
PDGFRB 1.9KIT 2
CSF1R 3.4PDGFRA 4.2FLT1 7.5
VEGFR2 8.1MUSK 10FLT4 16EPHB6 33
ABT‐869N
HN
NH2 NH NH
O
F
EPHB6 33FLT3 1.3KIT 4.8
PDGFRB 7.7RET 8CSF1R 10PDGFRA 11FLT1 41FLT4 41DDR1 81VEGFR2 87
AC220
NH NH
OO
N
N
NS
O NO
PDGFRA 0.51PDGFRB 0.57AURKC 1.3KIT 3.2FLT1 5.8
VEGFR2 5.9AURKB 11PLK4 16CSF1R 21
ABL1‐phosphorylated 36KIT 3 7
AG‐013736
NNH
N
S
O NH
KIT 3.7CSF1R 5.6ZAK 8
PDGFRB 9.1FLT4 9.7
PDGFRA 10FLT1 12RET 14
VEGFR2 26FLT3 71TIE1 0.29
AMG‐706
NH
O
N NH
N
NH
NCDKL2 0.52
ABL1‐nonphosphorylated 0.68DDR1 0.69FLT3 0.79LOK 0.92
CDC2L5 0.94CDK8 1.4CDK11 1.5TAK1 1.5
AST‐487NH
NN
NH
O
ON
N
NH
F
FF
1Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
PCTK2 0.95PCTK1 1.1CDKL5 2.6CDK7 2.8CDC2L5 3.2CDC2L2 5.2CDK9 5.8ICK 8.3
CDC2L1 8.4
AT‐7519NH
O NHN
ONH
NHCl
Cl
GSK3B 11MEK5 2.8AURKC 4.4AURKB 4.6FLT3 8.2KIT 17
PDGFRA 38PDGFRB 41EPHB6 50RET 80HIPK4 97
AZD‐1152HQPAO N
N
HN
NHN
NHO
FNHO
HIPK4 97PDGFRB 0.32
KIT 0.38PDGFRA 0.41FLT1 0.74
VEGFR2 1.1DDR1 1.7FLT4 4.3STK35 5.4RET 6.1CSF1R 13
AZD‐2171N
N
O
NH
FO
O
N
CSF1R 13MEK1 99MEK2 530EGFR 7000
AZD‐6244/ARRY‐886NH
F
NH OO
HO
NN
Cl
Br
PLK1 0.19PLK2 0.81PLK3 4
RPS6KA4(Kin.Dom.2‐C‐terminal) 12CAMKK1 22CAMKK2 23MYLK 97
PIP5K2C 110DAPK3 130FAK 150MEK5 1 8
BI‐2536
NH
O
O
NH N
N
N
N O
N
O MEK5 1.8BIKE 2.2
VEGFR2 2.9PKNB(M.tuberculosis) 3.6
FLT3 3.8TAK1 4.1TRKA 4.5
JAK1(JH2domain‐pseudokinase) 4.8MELK 4.9YSK4 5.2EGFR 0.25
BIBF‐1120 (derivative)
NHO
NH
N
O
NN
FERBB2 5ERBB4 6.3GAK 79BLK 220IRAK1 240EPHA6 340HIPK4 360PHKG2 470
ABL1‐phosphorylated 570
BIBW‐2992 N
N
NH
F
Cl
O
NH
O
N
O
2Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
p38‐alpha 0.45DDR1 1.9
p38‐gamma 2.9p38‐beta 7.2JNK2 7.3TIE1 8.3LOK 12TIE2 20DDR2 33
BIRB‐796 NN
NH NH
ON
O
O
p38‐delta 78IKK‐beta 130YSK4 260
CDC2L2 390CDC2L1 420ERK5 620CDK7 680MYLK4 700CDC2L5 800PCTK1 890ERN1 1000
BMS‐345541
N
N N
NHNH2
ERN1 1000CDKL5 1.7PCTK1 7.1PCTK2 13CDC2L5 23GSK3A 28CDK7 31GSK3B 37CDKL2 41PCTK3 44CDC2L2 48
BMS‐387032/SNS‐032N
O S
S
N
NH
O
NH
CDC2L2 48VEGFR2 5FLT1 10
PDGFRA 11STK35 26KIT 36
PDGFRB 50FLT4 56FGFR1 99FGFR2 110DDR1 160
BMS‐540215
NN
NOHO
O
NH
F
PHKG1 0.39YSK4 0.52LATS2 1SNARK 1MKNK2 1.4PLK4 1.5IRAK4 1.7PHKG2 1.7PKN2 1.8
JAK3(JH1domain‐catalytic) 2.3FLT3 0 64
CEP‐701NN
O
NHO
OH
HO
FLT3 0.64MLCK 2
PDGFRB 3.8KIT 7.5
MINK 9.1YSK4 12TNIK 24MEK5 32MAST1 40HPK1 44DDR1 13
CHIR‐258/TKI‐258
NH
NH
N N N
O
NH2F
EPHB6 43YSK4 54
GCN2(Kin.Dom.2,S808G) 55LOK 60ZAK 63CIT 87
TAOK2 140RET 150TIE1 150
CHIR‐265/RAF‐265
ON
N N
NH
NCF3
NH
CF3
3Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
EGFR 0.19ERBB4 6.5
ABL1‐phosphorylated 30BLK 45
ERBB2 56MEK5 60GAK 100MKK7 110
ABL1‐nonphosphorylated 210
CI‐1033
N
HN
O
N
N
O
HN Cl
F
O
p p yERBB3 210MEK1 120MEK2 370AURKC 1800PDGFRB 3100CAMK2A 3400CI‐1040
NH
NHO
F
F
O
Cl
I
JAK3(JH1domain‐catalytic) 0.16JAK2(JH1domain‐catalytic) 0.58JAK1(JH1domain‐catalytic) 1.6TYK2(JH1domain‐catalytic) 4.8
DCAMKL3 12TNK1 120PKN1 170SNARK 240ROCK2 420LCK 460
CP‐690550N
N NH
NN
ON
LCK 460MET 2.1ALK 3.3
MERTK 3.6ROS1 4.1EPHB6 6AXL 7.8LTK 12SLK 18
MST1R 25LCK 30
CrizotinibCl
F
ON
NH2
NN
Cl
NH
ABL1‐nonphosphorylated 0.029EPHB6 0.039
ABL1‐phosphorylated 0.046EPHA3 0.093ABL2 0.17LCK 0.2BLK 0.21SRC 0.21
EPHA5 0.24EPHA8 0.24EGFR 0 67
DasatinibNH
ClO
S
N
NH
N
N N N
OH
EGFR 0.67GAK 3.1LOK 19YSK4 25SLK 26
ABL1‐phosphorylated 76MEK5 96BLK 190ABL2 200ERBB4 230AXL 0.093
ErlotinibN
N
HN
O
O
O
O
DDR1 0.2MERTK 0.27HIPK4 0.51LOK 0.53RET 0.74TIE1 0.79FLT3 0.9
PDGFRB 0.96EPHA3 1
EXEL‐2880/GSK‐1363089
N
O
ONO
O
F NH NH
O OF
4Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMICK 0.69
CDK4‐cyclinD3 3.3CDK9 6.4CDKL5 7.1
CDK4‐cyclinD1 9CDK7 23MAK 28
TYK2(JH2domain‐pseudokinase) 35TNNI3K 55CDK11 57
FlavopiridolO
Cl
OOH
HO
N
OH
CDK11 57BRAF 0.19RAF1 6.6
CSNK1E 130YSK4 910MINK 1000RIOK2 1200LOK 1300SLK 1300
CSNK1D 1400BMPR1B 1800
GDC‐0879
OOH
NOH
NN
OH
N
PIK3CA 1.1PIK3CD 5PIK3CB 16PIK3CG 48PIK3C2B 130MTOR 200PIK3C2G 300
JAK1(JH2domain‐pseudokinase) 430HIPK2 520JNK3 560EGFR 1
GDC‐0941N
NS
NH
N
N
O
N
N
SO
O
EGFR 1GAK 13IRAK1 69YSK4 240
MKNK1 290HIPK4 310ERBB4 410CSNK1E 430LOK 470
ABL1‐phosphorylated 480ALK 0.55
Gefitinib
N
N
O
O
HN Cl
F
N
O
O F
LTK 1.1INSR 1.7IGF1R 7INSRR 8.6FER 9.3MYLK 11ROS1 15CLK2 16CLK1 21PLK1 0.094SNARK 23
GSK‐1838705A N
N NH
NH
NH
NH
O
N N
O
O
NH SNARK 23LOK 69
RSK2(Kin.Dom.1‐N‐terminal) 190PIM1 250NEK2 260
RSK4(Kin.Dom.1‐N‐terminal) 350BIKE 470PLK2 500
CAMK2D 620AKT2 2.1AKT1 2.2PRKCH 2 4
GSK‐461364A
NN
N
N
S NH2
O
FF
F
HOPRKCH 2.4AKT3 3PRKG2 3.1
PKNB(M.tuberculosis) 3.2PRKCE 5.3PRKX 7.2PAK7 8.9
PKAC‐beta 13
GSK‐690693N
N
N
OHN
N O
N
H2N
5Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMCSF1R 2.2TRKB 36TRKC 120TRKA 630
GW‐2580
N
N
NH2
H2N
O
O
O
MAP4K5 0.65EGFR 1.1ERBB4 2.4ERBB2 6MST3 6.5MST4 7.4ERBB3 7.7MAP4K3 7.7YSK1 12LOK 13
HKI‐272
N
HN
HN
O
ON
Cl
N
ON
DDR1 0.7ABL1‐nonphosphorylated 1.1
ABL2 10CSF1R 11KIT 13
PDGFRB 14DDR2 15
ABL1‐phosphorylated 21PDGFRA 31LCK 40
JAK2(JH1domain‐catalytic) 0 036
Imatinib
N
N
N NH NH
O
N
N
JAK2(JH1domain‐catalytic) 0.036TYK2(JH1domain‐catalytic) 0.9JAK3(JH1domain‐catalytic) 2JAK1(JH1domain‐catalytic) 3.4
MAP3K2 41CAMK2A 46ROCK2 52ROCK1 60
DCAMKL1 68DAPK1 72CSF1R 3.2
INCB018424
N N
HN N
N
N
NHKIT 3.6
AMPK‐alpha2 4.1AXL 5.3
TYK2(JH1domain‐catalytic) 5.8TAK1 7.2RET 9.2DDR1 9.4CHEK1 9.9
JAK2(JH1domain‐catalytic) 9.9PDGFRB 0.29PDGFRA 0.49
JNJ‐28312141
N
O
N
NH
ON
N
NO PDGFRA 0.49KIT 0.69
CSF1R 0.83EPHB6 5MEK5 7.4DDR1 12VEGFR2 18LOK 22SLK 60
DRAK1 2.9MLCK 4.3DRAK2 4 8
Ki‐20227
N
O
NH NH
O
S
O
O
N
NH
DRAK2 4.8YSK4 5.2BIKE 9.6
MAP4K2 11LOK 13SLK 13FLT3 15SRPK2 15
KW‐2449
NHN
O
6Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMEGFR 2.4ERBB2 7ERBB4 54PIK3C2B 670PIK4CB 940MEK5 1100SLK 3300RIPK2 3600LOK 4400MKK7 4400
Lapatinib
N
N
HN Cl
OF
O
NHSO
O
MKK7 4400GSK3B 8.3PRKCE 8.9PRKCD 25
RSK4(Kin.Dom.1‐N‐terminal) 25PRKCQ 36PRKCH 46ERK8 76
RSK2(Kin.Dom.1‐N‐terminal) 87DYRK1A 160PRKG2 170
LY‐317615
NHOO
NN
N
N
PRKCQ 2.5PRKCD 3.6PRKCE 11PIM3 12YSK4 48HIPK3 77ERK8 88TAOK3 97HIPK2 140
MAP3K3 170IKK‐beta 19
LY‐333531 N N
NH OO
O N
IKK‐beta 19PIK4CB 270
TYK2(JH2domain‐pseudokinase) 500CLK1 640CLK4 1000
IKK‐alpha 1000DYRK1A 2100CLK2 2300
PDGFRA 2.4
MLN‐120B
NH
NCl
O
NHO
N
KIT 2.7FLT3 3
PDGFRB 4.5CSF1R 4.9DDR2 120EGFR 410TRKA 450CLK1 630IRAK3 730AURKA 6.5DRAK2 8.1
MLN‐518 N
N
O NH
N
N
O
O
ON
DRAK2 8.1AURKC 26AURKB 43BLK 68
DRAK1 190FGR 220YES 260TIE2 300EPHB1 330DDR1 1.1
ABL1‐nonphosphorylated 10ZAK 11
MLN‐8054NH N
NN
F
F
Cl
HO
O
NF ZAK 11ABL1‐phosphorylated 13
ABL2 26KIT 29
DDR2 33p38‐beta 36EPHA8 37CSF1R 45
Nilotinib
N
N
NH
O
NH N
N
N
F
FF
7Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMPDGFRB 2
KIT 2.8PDGFRA 4.9CSF1R 7.9FLT1 14
VEGFR2 14FLT4 27TAOK3 45DDR1 57EPHB6 81
PazopanibN
NNH N
NN
S
O
NH2O
EPHB6 81ABL1‐phosphorylated 0.58
CSF1R 0.67ABL2 0.69SRC 0.71LCK 1.1
PDGFRB 1.4ABL1‐nonphosphorylated 1.5
BLK 1.5KIT 1.8
EPHB6 2
PD‐173955 N
N N OCl
Cl
NHS
MET 0.27SRPK1 41TAOK3 43BIKE 47GRK7 61HIPK3 63
CAMKK1 64DDR1 70
CAMKK2 73YSK4 78PIK3CA 1 5
PHA‐665752
NH
O
NH N
O
N
S
O
O
Cl
Cl
PIK3CA 1.5PIK3CB 1.7PIK3C2B 10MTOR 12PIK3CG 16PIK3CD 17PIK3C2G 41HIPK2 290HIPK3 310PIP5K2C 620PKN1 9.3
PI‐103
N
NO
N
N
OH
O
TBK1 9.3FLT3 11
JAK3(JH1domain‐catalytic) 12MLK1 15PKN2 15YSK4 15MLK3 17
CAMK2A 20MARK3 21MEK5 0.16
PFCDPK1(P.falciparum) 1.7
PKC‐412NN
NH O
O
NO
H
O
F PFCDPK1(P.falciparum) 1.7SRMS 21ZAK 41BRK 48FGR 62RAF1 170KIT 180
MEK4 190NEK11 190BMPR1B 2.1ACVRL1 2.9MTOR 3
PLX‐4720
N NH
O
F
FNH S
O OCl
OH
MTOR 3ACVR1 4RET 4.8YSK4 5.1MEK5 7.3ACVR2B 7.6PRKCE 9
JAK2(JH1domain‐catalytic) 11
PP‐242N
N NN
NH2 NH
8Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMKIT 5.1FLT1 9.6
PDGFRB 25CSF1R 45VEGFR2 62PDGFRA 96DDR1 270FLT4 330CDK11 1500FRK 1800
PTK‐787N
N
HN
N
Cl
FRK 1800FLT3 0.71STK16 1.7
GCN2(Kin.Dom.2,S808G) 3.3PDGFRB 3.3
JAK2(JH1domain‐catalytic) 3.5MLK2 3.8RET 4.1PLK4 4.2MLK1 4.3PLK3 5.1
R406NH
O
N NH N
N
O
F
NH
O
O
O
CDK2 0.53PCTK1 0.54CDK7 0.58
CDK4‐cyclinD1 0.61CDK4‐cyclinD3 0.81
PCTK2 0.86ICK 2.2CDK3 3.2
PFTAIRE2 7.2CDK5 7.4
p38‐alpha 12
R547
N
NNH NH2
ON
O F
F
SO
O
p38‐alpha 12GAK 19RIPK2 24NLK 25JNK3 35
CSNK1D 37p38‐beta 70CSNK1A1 75CSNK1E 100JNK2 130MET 0.19
SB‐203580N
NH
N
F
S
O
DYRK1A 780DYRK1B 1800JNK3 1900
PIP5K2C 3300JNK1 4200YSK4 6400
ABL1‐phosphorylated 0.057ABL1‐nonphosphorylated 0.12
SGX‐523N
N
N
N
S
NN
N
ABL1 nonphosphorylated 0.12MAP4K5 0.5
LCK 0.59ERBB3 0.77SRC 1GAK 1.3FRK 1.4ABL2 1.5STK35 2DDR1 1.5HIPK4 3.3ZAK 6 3
SKI‐606
N
O
O
HNCN
O
Cl Cl
NN
ZAK 6.3DDR2 6.6FLT3 13RET 13CSF1R 28KIT 28FLT1 31
PDGFRB 37
Sorafenib
NHNH
OCl
CF3
O
N
NH
O
9Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMSLK 0.024LOK 0.037
CAMKK1 0.039SNARK 0.086PHKG2 0.14CAMK2A 0.16CAMKK2 0.16MST2 0.18MST1 0.19TAOK3 0 22
Staurosporine NN
NH O
O
HNO
H
TAOK3 0.22PDGFRB 0.29FLT3 0.54KIT 0.68
PDGFRA 1.1VEGFR2 2.3CSF1R 3.6HUNK 3.7FLT1 4.7STK35 8.2YSK4 12
SU‐14813
NH
NH
H3C
CH3
NH
O
O
F
NO
OH
PDGFRB 0.075KIT 0.37FLT3 0.41
PDGFRA 0.79DRAK1 1VEGFR2 1.5FLT1 1.8CSF1R 2.5BIKE 5.5PHKG1 5.5ROS1 0 49
Sunitinib
NH
NH
F
O
O
NH N
ROS1 0.49ULK1 0.83
BMPR1B 0.85PLK4 0.93LTK 0.95ALK 1.1FAK 1.1PYK2 1.1SNARK 1.2FER 1.4
PIK3C2G 3.2
TAE‐684N
N
HN
Cl
SOO
NH
N
N
N
O
OHPIK3CG 5.3PIK3C2B 7.3TRPM6 7.9CLK2 43PIK3CA 59PIK3CB 80ADCK3 94RIPK4 97CLK4 130GAK 1.1
JAK2(JH1domain‐catalytic) 1.1
TG‐100‐115N
N N
N
H2N
NH2
OH
JAK2(JH1domain catalytic) 1.1DAPK3 1.2STK16 6.6
DCAMKL3 13FLT3 13DAPK1 16
JAK1(JH1domain‐catalytic) 18YSK4 19
TYK2(JH1domain‐catalytic) 21RIPK2 4.6EGFR 9.5DDR1 11
TG‐101348
N
N
NH
NH
ON
SNH
OO
Br
DDR1 11ABL1‐phosphorylated 16
LCK 17RET 34
ABL1‐nonphosphorylated 48MEK5 49EPHA6 50STK35 56
Vandetanib
N
NO
O
N
HN
F
10Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMAURKA 3.9ABL2 4AURKC 6.3FLT3 6.5
AURKB 7.4ABL1‐phosphorylated 7.5
PLK4 9.2ABL1‐nonphosphorylated 13
MLCK 15RIPK1 20
VX‐680/MK‐0457N
N
HN
SN
NH
O
NHN
NRIPK1 20
p38‐alpha 2.8p38‐beta 74DDR1 1100FGR 1300YES 1600LYN 1700ABL2 1900FYN 2100CSF1R 2600BLK 3100
VX‐745
SN
NN
Cl
OF
F
Cl
11Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
CLK2 0.51CLK4 0.53CLK1 1.4
DYRK1A 2.1DYRK1B 3.9PRKCH 9.5PRKCE 11PRKCQ 12CIT 13
A‐674563
NHN
N
O
NH2
PRKG2 19ABL1‐nonphosphorylated 2.1
CSF1R 7.6KIT 8.1
PDGFRB 8.4DDR1 8.7
PDGFRA 25DDR2 26LCK 31
ABL1‐phosphorylated 55LYN 61
AB‐1010 NHNH
O
N
S N
N
N
LYN 61FLT3 0.63
PDGFRB 1.9KIT 2
CSF1R 3.4PDGFRA 4.2FLT1 7.5
VEGFR2 8.1MUSK 10FLT4 16EPHB6 33
ABT‐869N
HN
NH2 NH NH
O
F
EPHB6 33FLT3 1.3KIT 4.8
PDGFRB 7.7RET 8CSF1R 10PDGFRA 11FLT1 41FLT4 41DDR1 81VEGFR2 87
AC220
NH NH
OO
N
N
NS
O NO
PDGFRA 0.51PDGFRB 0.57AURKC 1.3KIT 3.2FLT1 5.8
VEGFR2 5.9AURKB 11PLK4 16CSF1R 21
ABL1‐phosphorylated 36KIT 3 7
AG‐013736
NNH
N
S
O NH
KIT 3.7CSF1R 5.6ZAK 8
PDGFRB 9.1FLT4 9.7
PDGFRA 10FLT1 12RET 14
VEGFR2 26FLT3 71TIE1 0.29
AMG‐706
NH
O
N NH
N
NH
NCDKL2 0.52
ABL1‐nonphosphorylated 0.68DDR1 0.69FLT3 0.79LOK 0.92
CDC2L5 0.94CDK8 1.4CDK11 1.5TAK1 1.5
AST‐487NH
NN
NH
O
ON
N
NH
F
FF
1Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
PCTK2 0.95PCTK1 1.1CDKL5 2.6CDK7 2.8CDC2L5 3.2CDC2L2 5.2CDK9 5.8ICK 8.3
CDC2L1 8.4
AT‐7519NH
O NHN
ONH
NHCl
Cl
GSK3B 11MEK5 2.8AURKC 4.4AURKB 4.6FLT3 8.2KIT 17
PDGFRA 38PDGFRB 41EPHB6 50RET 80HIPK4 97
AZD‐1152HQPAO N
N
HN
NHN
NHO
FNHO
HIPK4 97PDGFRB 0.32
KIT 0.38PDGFRA 0.41FLT1 0.74
VEGFR2 1.1DDR1 1.7FLT4 4.3STK35 5.4RET 6.1CSF1R 13
AZD‐2171N
N
O
NH
FO
O
N
CSF1R 13MEK1 99MEK2 530EGFR 7000
AZD‐6244/ARRY‐886NH
F
NH OO
HO
NN
Cl
Br
PLK1 0.19PLK2 0.81PLK3 4
RPS6KA4(Kin.Dom.2‐C‐terminal) 12CAMKK1 22CAMKK2 23MYLK 97
PIP5K2C 110DAPK3 130FAK 150MEK5 1 8
BI‐2536
NH
O
O
NH N
N
N
N O
N
O MEK5 1.8BIKE 2.2
VEGFR2 2.9PKNB(M.tuberculosis) 3.6
FLT3 3.8TAK1 4.1TRKA 4.5
JAK1(JH2domain‐pseudokinase) 4.8MELK 4.9YSK4 5.2EGFR 0.25
BIBF‐1120 (derivative)
NHO
NH
N
O
NN
FERBB2 5ERBB4 6.3GAK 79BLK 220IRAK1 240EPHA6 340HIPK4 360PHKG2 470
ABL1‐phosphorylated 570
BIBW‐2992 N
N
NH
F
Cl
O
NH
O
N
O
2Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
p38‐alpha 0.45DDR1 1.9
p38‐gamma 2.9p38‐beta 7.2JNK2 7.3TIE1 8.3LOK 12TIE2 20DDR2 33
BIRB‐796 NN
NH NH
ON
O
O
p38‐delta 78IKK‐beta 130YSK4 260
CDC2L2 390CDC2L1 420ERK5 620CDK7 680MYLK4 700CDC2L5 800PCTK1 890ERN1 1000
BMS‐345541
N
N N
NHNH2
ERN1 1000CDKL5 1.7PCTK1 7.1PCTK2 13CDC2L5 23GSK3A 28CDK7 31GSK3B 37CDKL2 41PCTK3 44CDC2L2 48
BMS‐387032/SNS‐032N
O S
S
N
NH
O
NH
CDC2L2 48VEGFR2 5FLT1 10
PDGFRA 11STK35 26KIT 36
PDGFRB 50FLT4 56FGFR1 99FGFR2 110DDR1 160
BMS‐540215
NN
NOHO
O
NH
F
PHKG1 0.39YSK4 0.52LATS2 1SNARK 1MKNK2 1.4PLK4 1.5IRAK4 1.7PHKG2 1.7PKN2 1.8
JAK3(JH1domain‐catalytic) 2.3FLT3 0 64
CEP‐701NN
O
NHO
OH
HO
FLT3 0.64MLCK 2
PDGFRB 3.8KIT 7.5
MINK 9.1YSK4 12TNIK 24MEK5 32MAST1 40HPK1 44DDR1 13
CHIR‐258/TKI‐258
NH
NH
N N N
O
NH2F
EPHB6 43YSK4 54
GCN2(Kin.Dom.2,S808G) 55LOK 60ZAK 63CIT 87
TAOK2 140RET 150TIE1 150
CHIR‐265/RAF‐265
ON
N N
NH
NCF3
NH
CF3
3Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nM
EGFR 0.19ERBB4 6.5
ABL1‐phosphorylated 30BLK 45
ERBB2 56MEK5 60GAK 100MKK7 110
ABL1‐nonphosphorylated 210
CI‐1033
N
HN
O
N
N
O
HN Cl
F
O
p p yERBB3 210MEK1 120MEK2 370AURKC 1800PDGFRB 3100CAMK2A 3400CI‐1040
NH
NHO
F
F
O
Cl
I
JAK3(JH1domain‐catalytic) 0.16JAK2(JH1domain‐catalytic) 0.58JAK1(JH1domain‐catalytic) 1.6TYK2(JH1domain‐catalytic) 4.8
DCAMKL3 12TNK1 120PKN1 170SNARK 240ROCK2 420LCK 460
CP‐690550N
N NH
NN
ON
LCK 460MET 2.1ALK 3.3
MERTK 3.6ROS1 4.1EPHB6 6AXL 7.8LTK 12SLK 18
MST1R 25LCK 30
CrizotinibCl
F
ON
NH2
NN
Cl
NH
ABL1‐nonphosphorylated 0.029EPHB6 0.039
ABL1‐phosphorylated 0.046EPHA3 0.093ABL2 0.17LCK 0.2BLK 0.21SRC 0.21
EPHA5 0.24EPHA8 0.24EGFR 0 67
DasatinibNH
ClO
S
N
NH
N
N N N
OH
EGFR 0.67GAK 3.1LOK 19YSK4 25SLK 26
ABL1‐phosphorylated 76MEK5 96BLK 190ABL2 200ERBB4 230AXL 0.093
ErlotinibN
N
HN
O
O
O
O
DDR1 0.2MERTK 0.27HIPK4 0.51LOK 0.53RET 0.74TIE1 0.79FLT3 0.9
PDGFRB 0.96EPHA3 1
EXEL‐2880/GSK‐1363089
N
O
ONO
O
F NH NH
O OF
4Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMICK 0.69
CDK4‐cyclinD3 3.3CDK9 6.4CDKL5 7.1
CDK4‐cyclinD1 9CDK7 23MAK 28
TYK2(JH2domain‐pseudokinase) 35TNNI3K 55CDK11 57
FlavopiridolO
Cl
OOH
HO
N
OH
CDK11 57BRAF 0.19RAF1 6.6
CSNK1E 130YSK4 910MINK 1000RIOK2 1200LOK 1300SLK 1300
CSNK1D 1400BMPR1B 1800
GDC‐0879
OOH
NOH
NN
OH
N
PIK3CA 1.1PIK3CD 5PIK3CB 16PIK3CG 48PIK3C2B 130MTOR 200PIK3C2G 300
JAK1(JH2domain‐pseudokinase) 430HIPK2 520JNK3 560EGFR 1
GDC‐0941N
NS
NH
N
N
O
N
N
SO
O
EGFR 1GAK 13IRAK1 69YSK4 240
MKNK1 290HIPK4 310ERBB4 410CSNK1E 430LOK 470
ABL1‐phosphorylated 480ALK 0.55
Gefitinib
N
N
O
O
HN Cl
F
N
O
O F
LTK 1.1INSR 1.7IGF1R 7INSRR 8.6FER 9.3MYLK 11ROS1 15CLK2 16CLK1 21PLK1 0.094SNARK 23
GSK‐1838705A N
N NH
NH
NH
NH
O
N N
O
O
NH SNARK 23LOK 69
RSK2(Kin.Dom.1‐N‐terminal) 190PIM1 250NEK2 260
RSK4(Kin.Dom.1‐N‐terminal) 350BIKE 470PLK2 500
CAMK2D 620AKT2 2.1AKT1 2.2PRKCH 2 4
GSK‐461364A
NN
N
N
S NH2
O
FF
F
HOPRKCH 2.4AKT3 3PRKG2 3.1
PKNB(M.tuberculosis) 3.2PRKCE 5.3PRKX 7.2PAK7 8.9
PKAC‐beta 13
GSK‐690693N
N
N
OHN
N O
N
H2N
5Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMCSF1R 2.2TRKB 36TRKC 120TRKA 630
GW‐2580
N
N
NH2
H2N
O
O
O
MAP4K5 0.65EGFR 1.1ERBB4 2.4ERBB2 6MST3 6.5MST4 7.4ERBB3 7.7MAP4K3 7.7YSK1 12LOK 13
HKI‐272
N
HN
HN
O
ON
Cl
N
ON
DDR1 0.7ABL1‐nonphosphorylated 1.1
ABL2 10CSF1R 11KIT 13
PDGFRB 14DDR2 15
ABL1‐phosphorylated 21PDGFRA 31LCK 40
JAK2(JH1domain‐catalytic) 0 036
Imatinib
N
N
N NH NH
O
N
N
JAK2(JH1domain‐catalytic) 0.036TYK2(JH1domain‐catalytic) 0.9JAK3(JH1domain‐catalytic) 2JAK1(JH1domain‐catalytic) 3.4
MAP3K2 41CAMK2A 46ROCK2 52ROCK1 60
DCAMKL1 68DAPK1 72CSF1R 3.2
INCB018424
N N
HN N
N
N
NHKIT 3.6
AMPK‐alpha2 4.1AXL 5.3
TYK2(JH1domain‐catalytic) 5.8TAK1 7.2RET 9.2DDR1 9.4CHEK1 9.9
JAK2(JH1domain‐catalytic) 9.9PDGFRB 0.29PDGFRA 0.49
JNJ‐28312141
N
O
N
NH
ON
N
NO PDGFRA 0.49KIT 0.69
CSF1R 0.83EPHB6 5MEK5 7.4DDR1 12VEGFR2 18LOK 22SLK 60
DRAK1 2.9MLCK 4.3DRAK2 4 8
Ki‐20227
N
O
NH NH
O
S
O
O
N
NH
DRAK2 4.8YSK4 5.2BIKE 9.6
MAP4K2 11LOK 13SLK 13FLT3 15SRPK2 15
KW‐2449
NHN
O
6Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMEGFR 2.4ERBB2 7ERBB4 54PIK3C2B 670PIK4CB 940MEK5 1100SLK 3300RIPK2 3600LOK 4400MKK7 4400
Lapatinib
N
N
HN Cl
OF
O
NHSO
O
MKK7 4400GSK3B 8.3PRKCE 8.9PRKCD 25
RSK4(Kin.Dom.1‐N‐terminal) 25PRKCQ 36PRKCH 46ERK8 76
RSK2(Kin.Dom.1‐N‐terminal) 87DYRK1A 160PRKG2 170
LY‐317615
NHOO
NN
N
N
PRKCQ 2.5PRKCD 3.6PRKCE 11PIM3 12YSK4 48HIPK3 77ERK8 88TAOK3 97HIPK2 140
MAP3K3 170IKK‐beta 19
LY‐333531 N N
NH OO
O N
IKK‐beta 19PIK4CB 270
TYK2(JH2domain‐pseudokinase) 500CLK1 640CLK4 1000
IKK‐alpha 1000DYRK1A 2100CLK2 2300
PDGFRA 2.4
MLN‐120B
NH
NCl
O
NHO
N
KIT 2.7FLT3 3
PDGFRB 4.5CSF1R 4.9DDR2 120EGFR 410TRKA 450CLK1 630IRAK3 730AURKA 6.5DRAK2 8.1
MLN‐518 N
N
O NH
N
N
O
O
ON
DRAK2 8.1AURKC 26AURKB 43BLK 68
DRAK1 190FGR 220YES 260TIE2 300EPHB1 330DDR1 1.1
ABL1‐nonphosphorylated 10ZAK 11
MLN‐8054NH N
NN
F
F
Cl
HO
O
NF ZAK 11ABL1‐phosphorylated 13
ABL2 26KIT 29
DDR2 33p38‐beta 36EPHA8 37CSF1R 45
Nilotinib
N
N
NH
O
NH N
N
N
F
FF
7Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMPDGFRB 2
KIT 2.8PDGFRA 4.9CSF1R 7.9FLT1 14
VEGFR2 14FLT4 27TAOK3 45DDR1 57EPHB6 81
PazopanibN
NNH N
NN
S
O
NH2O
EPHB6 81ABL1‐phosphorylated 0.58
CSF1R 0.67ABL2 0.69SRC 0.71LCK 1.1
PDGFRB 1.4ABL1‐nonphosphorylated 1.5
BLK 1.5KIT 1.8
EPHB6 2
PD‐173955 N
N N OCl
Cl
NHS
MET 0.27SRPK1 41TAOK3 43BIKE 47GRK7 61HIPK3 63
CAMKK1 64DDR1 70
CAMKK2 73YSK4 78PIK3CA 1 5
PHA‐665752
NH
O
NH N
O
N
S
O
O
Cl
Cl
PIK3CA 1.5PIK3CB 1.7PIK3C2B 10MTOR 12PIK3CG 16PIK3CD 17PIK3C2G 41HIPK2 290HIPK3 310PIP5K2C 620PKN1 9.3
PI‐103
N
NO
N
N
OH
O
TBK1 9.3FLT3 11
JAK3(JH1domain‐catalytic) 12MLK1 15PKN2 15YSK4 15MLK3 17
CAMK2A 20MARK3 21MEK5 0.16
PFCDPK1(P.falciparum) 1.7
PKC‐412NN
NH O
O
NO
H
O
F PFCDPK1(P.falciparum) 1.7SRMS 21ZAK 41BRK 48FGR 62RAF1 170KIT 180
MEK4 190NEK11 190BMPR1B 2.1ACVRL1 2.9MTOR 3
PLX‐4720
N NH
O
F
FNH S
O OCl
OH
MTOR 3ACVR1 4RET 4.8YSK4 5.1MEK5 7.3ACVR2B 7.6PRKCE 9
JAK2(JH1domain‐catalytic) 11
PP‐242N
N NN
NH2 NH
8Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMKIT 5.1FLT1 9.6
PDGFRB 25CSF1R 45VEGFR2 62PDGFRA 96DDR1 270FLT4 330CDK11 1500FRK 1800
PTK‐787N
N
HN
N
Cl
FRK 1800FLT3 0.71STK16 1.7
GCN2(Kin.Dom.2,S808G) 3.3PDGFRB 3.3
JAK2(JH1domain‐catalytic) 3.5MLK2 3.8RET 4.1PLK4 4.2MLK1 4.3PLK3 5.1
R406NH
O
N NH N
N
O
F
NH
O
O
O
CDK2 0.53PCTK1 0.54CDK7 0.58
CDK4‐cyclinD1 0.61CDK4‐cyclinD3 0.81
PCTK2 0.86ICK 2.2CDK3 3.2
PFTAIRE2 7.2CDK5 7.4
p38‐alpha 12
R547
N
NNH NH2
ON
O F
F
SO
O
p38‐alpha 12GAK 19RIPK2 24NLK 25JNK3 35
CSNK1D 37p38‐beta 70CSNK1A1 75CSNK1E 100JNK2 130MET 0.19
SB‐203580N
NH
N
F
S
O
DYRK1A 780DYRK1B 1800JNK3 1900
PIP5K2C 3300JNK1 4200YSK4 6400
ABL1‐phosphorylated 0.057ABL1‐nonphosphorylated 0.12
SGX‐523N
N
N
N
S
NN
N
ABL1 nonphosphorylated 0.12MAP4K5 0.5
LCK 0.59ERBB3 0.77SRC 1GAK 1.3FRK 1.4ABL2 1.5STK35 2DDR1 1.5HIPK4 3.3ZAK 6 3
SKI‐606
N
O
O
HNCN
O
Cl Cl
NN
ZAK 6.3DDR2 6.6FLT3 13RET 13CSF1R 28KIT 28FLT1 31
PDGFRB 37
Sorafenib
NHNH
OCl
CF3
O
N
NH
O
9Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMSLK 0.024LOK 0.037
CAMKK1 0.039SNARK 0.086PHKG2 0.14CAMK2A 0.16CAMKK2 0.16MST2 0.18MST1 0.19TAOK3 0 22
Staurosporine NN
NH O
O
HNO
H
TAOK3 0.22PDGFRB 0.29FLT3 0.54KIT 0.68
PDGFRA 1.1VEGFR2 2.3CSF1R 3.6HUNK 3.7FLT1 4.7STK35 8.2YSK4 12
SU‐14813
NH
NH
H3C
CH3
NH
O
O
F
NO
OH
PDGFRB 0.075KIT 0.37FLT3 0.41
PDGFRA 0.79DRAK1 1VEGFR2 1.5FLT1 1.8CSF1R 2.5BIKE 5.5PHKG1 5.5ROS1 0 49
Sunitinib
NH
NH
F
O
O
NH N
ROS1 0.49ULK1 0.83
BMPR1B 0.85PLK4 0.93LTK 0.95ALK 1.1FAK 1.1PYK2 1.1SNARK 1.2FER 1.4
PIK3C2G 3.2
TAE‐684N
N
HN
Cl
SOO
NH
N
N
N
O
OHPIK3CG 5.3PIK3C2B 7.3TRPM6 7.9CLK2 43PIK3CA 59PIK3CB 80ADCK3 94RIPK4 97CLK4 130GAK 1.1
JAK2(JH1domain‐catalytic) 1.1
TG‐100‐115N
N N
N
H2N
NH2
OH
JAK2(JH1domain catalytic) 1.1DAPK3 1.2STK16 6.6
DCAMKL3 13FLT3 13DAPK1 16
JAK1(JH1domain‐catalytic) 18YSK4 19
TYK2(JH1domain‐catalytic) 21RIPK2 4.6EGFR 9.5DDR1 11
TG‐101348
N
N
NH
NH
ON
SNH
OO
Br
DDR1 11ABL1‐phosphorylated 16
LCK 17RET 34
ABL1‐nonphosphorylated 48MEK5 49EPHA6 50STK35 56
Vandetanib
N
NO
O
N
HN
F
10Nature Biotechnology: doi:10.1038/nbt.1990
Supplementary Table 2. Compound structures and highest affinity target kinases (excluding mutants)
Compound Structure Kinase Kd, nMAURKA 3.9ABL2 4AURKC 6.3FLT3 6.5
AURKB 7.4ABL1‐phosphorylated 7.5
PLK4 9.2ABL1‐nonphosphorylated 13
MLCK 15RIPK1 20
VX‐680/MK‐0457N
N
HN
SN
NH
O
NHN
NRIPK1 20
p38‐alpha 2.8p38‐beta 74DDR1 1100FGR 1300YES 1600LYN 1700ABL2 1900FYN 2100CSF1R 2600BLK 3100
VX‐745
SN
NN
Cl
OF
F
Cl
11Nature Biotechnology: doi:10.1038/nbt.1990
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