JAK2 inhibitor

Z BioInf

Charakterystyka wybranych niskocząsteczkowych inhibitorów domeny kinazowej JAK2

Lp. inhibitor
(inne hamowane kinazy)
klasa chemiczna test enzym. test komórkowy            literatura           
IC50 (µM)         linia komórkowa         GI50 (µM)
1 AG490
(EGFR, PDGFR)
tyrphostin 36.4
48
145.3
B-precursor (KOCL-33,-45,
-50,-69,KOPN-30bi,-55bi,
-57bi,-72bi,KOPN-32,-62,
-84,NALM 6)
T-precursor (KOPT-K1,-5,
-11,Jurkat)
Ba/F3:JAK2V617F
HEL (JAK2V617F)
SET-2 (JAK2V617F/wt)
XG-1
XG-2
U266
MDAH2774
Caov-3
MDA-MB-468
-



-

1.0
>20.0
>20.0
14.8
12.9
26.0
-
-
-
Gazit et al. 1989
Gazit et al. 1991
Meydan et al. 1996
Vos et al. 2000
Miyamoto et al. 2001
Burke et al. 2001
Duhé et al. 2002
Reddy et al. 2010
Jatiani et al. 2010
2 LS104
(BCR-ABL)
tyrphostin 2.52
0.1-0.6
Ba/F3:EpoR,JAK2V617F
Ba/F3:EpoR,JAK2wt
HEL
1.5
10.0
Grunberger et al. 2003
Lipka et al. 2008
3 WP1066 tyrphostin - HEL 2.3 Verstovsek et al. 2008
4 ON044580
(BCR-ABL)
α-benzoyl styryl benzyl sulfide 0.9-1.2
4.2
Ba/F3:JAK2V617F
HEL
SET-2
0.25
0.90
3.00
Reddy et al. 2010
Jatiani et al. 2010
Samanta et al. 2010
5 lestaurtinib
(CEP701)
(FLT3,JAK3)
indolocarbazole 0.001 HEL 0.03-0.10 Hexner et al. 2008
Santos et al. 2010
6 Gö6976
(JAK3, FLT3, PKCα,β1)
indolocarbazole 0.13 32D
32D:TEL-JAK2
FDCP1
TF-1
Mo7E
HEL
0.093
0.242
-
-
-
-
Grandage et al. 2006
7 TG02
(CDKs, TYK2, FLT3, TYRO3, ERK5, p38δ, Fms, Lck, Fyn, JAK1)
pyrimidine - HEL
SET-2
Ba/F3:JAK2wt
Ba/F3:JAK2V617F
Karpas-1106P
32D
0.202
0.231
0.156
0.099
0.068
0.098
Goh et al. 2012
Pallis et al. 2012
8 TG101209
(FLT3, RET, JAK3)
pyrimidine 0.006 Ba/F3:JAK2V617F
HEL
multiple myeloma cell lines (RPMI8226, MM1S, OPM2, NCI-H929, Dox40, MM1R, LR5)
0.2
2-5
-
Pardanani et al. 2007
Wang and Fiskus et al. 2009
Ramakrishnan et al. 2010
9 TG101348
(FLT3, RET, JAK1, JAK3, TYK2)
pyrimidine 0.003 Ba/F3:JAK2V617F
HEL
0.270
0.305
Wernig et al. 2008
Pardanani et al. 2009
Pardanani et al. 2011
10 R723
(JAK3, TYK2, FLT3, PRKD2, TBK1, SYK, PAK4, DAPK3, PRKD1, MYLK2, PRKCN, STK22D, IKBKE)
pyrimidine 0.002 Ba/F3:JAK2V617F 0.13-0.20 Shide et al. 2009
Shide et al. 2011
11 INCB018424
(JAK1, JAK3, TYK2)
pyrrolopyrimidine 0.0045 - - Fridman et al. 2007
Verstovsek et al. 2007
Verstovsek et al. 2008
Verstovsek et al. 2010
Quintás-Cardama et al. 2010
Mesa et al. 2011
12 INCB16562
(JAK1, JAK3)
pyrrolopyrimidine 0.0003 Ba/F3:JAK2V617F
Ba/F3:JAK2K539L
Ba/F3:MPLW515L
Ba/F3:TEL-JAK2
SET-2
UKE-1
0.177
0.406
0.600
0.168
0.046
0.573
Koppikar et al. 2010
13 CP690550
(JAK1, JAK3, TYK2)
pyrrolopyrimidine 0.0041
0.011
0.012
0.020
FDCP-EpoR,JAK2wt
FDCP-EpoR,JAK2V617F
2.1
0.25
Changelian et al. 2003
Chen et al. 2006
Clark et al. 2007
Manshouri et al. 2008
Meyer et al. 2010
Thoma et al. 2011
14 AZD1480
(JAK1, JAK3, TRKA, AuroraA, FLT4, FGFR1, ARK5)
pyrazolopyrimidine 0.003 Ba/F3:TEL-JAK2
SET-2
UKE1
HEL
0.06
0.016
0.054
0.39
Hedvat et al. 2009
Ioannidis et al. 2011
15 CYT387
(JAK1, TYK2, CDK2/cyclinA, JNK1, PRKCN, PRKD1, ROCK2, TBK1)
aminopyrimidine 0.018 Ba/F3:EpoR,JAK2V617F
32D:EpoR,JAK2V617F
HEL
TF-1
U266
CHRF-288-11:JAK2T875N
Ba/F3:TEL-JAK2
0.5
1.5
1.5
1.25
0.75
0.001
0.724
Pardanani et al. 2009
Tyner et al. 2010
16 SGI1252
(JAK1, JAK3, TYK2, YES, FLT3, ABL, SRC, LCK)
diaminopyrimidine 0.0054
0.002
0.0197
FDCP-EpoR,JAK2wt
FDCP-EpoR,JAK2V617F
HEL
SET-2
UKE-1
0.074
0.110
0.441
0.055
0.089
Olsen et al. 2008
Riaz Ahmed et al. 2008
Riaz Ahmed et al. 2011
17 SB1518
(FLT3, JAK1, JAK3, TYK2)
aminopyrimidine macrocycle 0.023
0.019
Ba/F3:JAK2V617F
HEL
SET-2
Karpas-1106P
U266
0.16
1.726
0.217
0.348
1.350
Hart et al. 2011
William et al. 2011
18 "38"
(JAK1, TYK2, JAK3, MEKK2, MEKK3)
8-oxo-pyridopyrimidine 0.001 TF-1-EPO (IC50) 0.115 Labadie et al. 2013
19 Z3 pyridine 15.0
28.0
HEL - Sayyah et al. 2008
20 "25"
(JAK1, GAK, YSK4)
thienopyridine 0.002 Ba/F3:TEL-JAK2 (IC50) 1.62 Schenkel et al. 2011
21 "65"
(JAK1, cSRC, TRKA, ACK1, FMS, FYN, FLT3, HCK, RET, BMX, LYN, FGR, LCK, ARK5, BTK, YES, PTK5, TRKB, CaMKIIδ,γ, PRK2, ARG, MLK1, ALK)
pyridoindolcarboxamide 0.0008 irf1-bla HEL (IC50) 0.025 Lim et al. 2011
22 AT9283
(AuroraK, JAK3, FLT3, ABL)
pyrazole benzimidazole 0.0012 HEL (JAK2V617F)
SET-2 (JAK2V617F/wt)
Ba/F3:ETV6-JAK2
Ba/F3-IL-3
TF-1-IL-3
CMK (JAK2A572V)
0.110
0.057
0.016
0.017
0.040
0.026
Howard et al. 2009
Dawson et al. 2010
23 AZ960
(TRKA, AuroraA, ARK5, ALK, CaMKII, FLT4, FGFR1, LIMK1, BrSK2, FAK)
pyrazole nicotinonitrile 0.003 SET-2 (JAK2V617F/wt)
Ba/F3:TEL-JAK2
HTLV-1 infected T cells (MT-1, MT-2)
0.033
0.025
-
Gozgit et al. 2008
Yang et al. 2010
24 CMP6
(JAK1, JAK3, TYK2)
pyridone tetracycle 0.001 CTLL-2
B9
U266
KMS11
0.052-0.1
0.25
-
-
Thompson et al. 2002
Lucet et al. 2006
Pedranzini et al. 2006
25 "13" sulfonamide aminoindazole 0.078 - - Antonysamy et al. 2009
26 comp 9
(JAK3, ALK, cKIT, GCK)
polycyclic azaindole 0.001 TF-1-GMCSF (IC50)
HT2-IL2 (IC50)
0.27
1.53
Wang et al. 2009
27 "15a" polycyclic azaindole 0.0008 TF-1-GMCSF (IC50) 0.16 Wang et al. 2010
28 "40"
(JAK3)
aminopyrazolopyrimidine 0.0002 TF-1-GMCSF (IC50)
HT2-IL2 (IC50)
0.16
3.2
Ledeboer et al. 2009
29 "29"
(JAK1, JAK3)
pyrrolotriazine aminopyrrazole 0.0018 SET-2 0.11 Harikrishnan et al. 2011
30 atiprimod
(JAK3)
azaspirane - FDCP-EpoR,JAK2wt
FDCP-EpoR,JAK2V617F
SET-2
0.69
0.42
0.53
Hamasaki et al. 2005
Quintás-Cardama et al. 2011
31 G6 stilbenoid
(diaryleten)
0.060 Ba/F3:EpoR,JAK2V617F
HEL
-
4.0
Kiss et al. 2009
Majumder et al. 2010
Kirabo et al. 2011
32 NVP-BSK805
(JAK1, TYK2, ABL)
diarylquinoxaline 0.00048
0.00058
0.00056
Ba/F3:JAK2V617F
SET-2
MB-02
UKE-1
MUTZ-8
0.039
0.051
0.064
0.071
0.331
Baffert et al. 2010
33 "26"
(ABL)
diarylquinoxaline 0.0073 SET-2 0.088 Pissot-Soldermann et al. 2010
34 hexabromo cyclohexane cyclohexane low µM γ-2A - Sandberg et al. 2005
35 XL019
(JAK1, JAK3, FLT3, PDGFRB, cKIT)
arylaminopyrimidine 0.002 HEL - Paquette et al. 2008
Shah et al. 2008
Forsyth et al. 2012
36 CEP33779
(JAK1, JAK3)
triazolopyridine 0.0018 irf1-bla TF-1 (IC50) 0.061 Dugan et al. 2012
37 "29"
(JAK1, JAK3, TYK2)
triazolopyridine 0.0017 SET-2 (IC50) 0.212 Siu et al. 2013
38 "6"
(JAK1, JAK3, TYK2)
imidazopyrrolopyridine 0.0021 TF-1-EPO (IC50) 0.097 Zak et al. 2012
39 "7"
(JAK1, JAK3, TYK2)
imidazopyrrolopyridine 0.0012 TF-1-EPO (IC50) 0.86 Kulagowski et al. 2012
40 "31"
(JAK1, JAK3, TYK2)
imidazopyrrolopyridine 0.068 TF-1-EPO (IC50) 7.68 Zak et al. 2013
41 "46"
(JAK1, TYK2)
pyridine amide 0.028 TF-1-EPO (IC50) 1.7 Liang et al. 2013
42 "7j"
(JAK1, JAK3, TYK2)
pyrazolopyrimidine 0.0001 SET-2 (IC50)
TF-1-EPO (IC50)
0.0039
0.0074
Hanan et al. 2012
43 "6"
(JAK3)
pyrazolopyrimidine amine 0.003 Ba/F3:TEL-JAK2
SET-2
UKE1
0.006
0.078
0.050
Guan et al. 2013
44 "19a"
(JAK1, JAK3, CK2α2, KDR, ABL, FGR, TRKA, FLT4, FLT3, RET, ALK, FGFR1, AuroraA, LIMK1)
methylimidazole 0.002 Ba/F3:TEL-JAK2
SET-2
UKE1
0.012
0.014
0.055
Su et al. 2014
45 NS-018
(JAK1, JAK3, TYK2, SRC, FYN, YES, LYNa, FGR, LCK, HCK, ABL, FLT3)
pyrazinopyridine diamine 0.00072 Ba/F3:JAK2V617F
Ba/F3:TEL-JAK2
Ba/F3:MPLW515L
SET-2
Ba/F3:TEL-JAK3
MV4-11(FLT3-ITD)
0.060 0.011 0.061 0.120 0.800 0.730 Nakaya et al. 2011
Nakaya et al. 2014
Osobiste