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L o g [R X C 0 0 5 ] (M )
% i
nh
ibit
ion
-1 4 -1 2 -1 0 -8 -6 -4
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
B T K W T
B T K C 4 8 1 S
-1 1 -1 0 -9 -8 -7 -6 -5 -4
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
L o g [R X C 0 0 5 ] (M )
B T K W T
B T K C 4 8 1 S
% i
nh
ibit
ion
-1 2 -1 0 -8 -6 -4
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
lo g [R X C 0 0 5 ] (M )
% o
f a
cti
va
ted
B-c
ell
s
(Ig
M-s
tim
ula
ted
CD
19
+ C
D6
9+
ce
lls
)
-1 2 -1 0 -8 -6 -4
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
lo g [R X C 0 0 5 ] (M )
% o
f a
cti
va
ted
B-c
ell
s
(Ig
D-s
tim
ula
ted
CD
19
+ C
D6
9+
ce
lls
)
pBTK
BTK
B-Actin
γ γ
α
Cell line
OCI-Ly10 (pIC50) 8.2± 9.3±0.2 8.3±0.1 8.4±0.2
TMD8 (pIC50) 8.3± 9.1±0.2 8.3 (N=2) 8.2 (N=2)
IgM stimulation
pBtk
gapdh
Btk
00251868 CLL
Veh
icle
20
0 n
MR
XC
00
5
50
0 n
MIb
ruti
nib
Veh
icle
DC
9 (
+ co
ntr
ol)
50
0 n
MR
XC
00
5
10
0 n
MR
XC
00
5
0 1 0 2 0 3 0 4 01 .0
1 .5
2 .0
D a y s p o s t la s t t r e a t m e n t
RT
V (
Re
lati
ve
Tu
mo
ur
Vo
lum
e)
****
***
***
* * * * p < 0 .0 0 0 1
* * * p < 0 .0 0 1
0 2 0 4 0 6 0
D a y s
Tu
mo
ur
vo
lum
e (
mm
3)
V e h ic le B ID
R X C 0 0 5 [1 0 m g / k g ] B ID
R X C 0 0 5 [5 0 m g / k g ] B ID
Ib r u t in ib [1 0 m g / k g ] Q D
2 0 0
3 0 0
4 0 0
5 0 0
1 5 0
1 0 0T re a tm e n t R e g r o w th
0 1 0 2 0 3 0
T r e a t m e n t t im e (D a y s )
Tu
mo
ur
vo
lum
e (
mm
3)
V e h ic le B ID
R X C 0 0 5 1 0 m g / k g B ID
R X C 0 0 5 5 0 m g / k g B ID
Ib r u t in ib 1 0 m g / k g Q D
2 0 0
3 0 0
4 0 0
5 0 0
1 5 0
1 0 0
****
* * * * p < 0 .0 0 0 1
***
* * * p < 0 .0 0 1
0 7 1 4 2 1
T r e a t m e n t t im e (d a y s )
Tu
mo
ur
vo
lum
e (
mm
3)
V e h ic le
R X C 0 0 5 3 0 m g / k g B ID
1 0 0
2 0 0
4 0 0
R X C 0 0 5 1 0 m g / k g B ID
8 0 0
1 0 0 0
* * * * p < 0 .0 0 0 1
****
****