reduced global levels of 5hmC in IDH mutants, TETs are thought to play a
contributory role in the tumorigenicity of IDH mutant cells. Other TCA cycle
intermediates, such as succinate (31) and fumarate (32), can also accumulate as a
result of tumour-associated mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) [168]. Biochemical assays using
HO
O
H
N
O
O
OH
NOG, 30
N-oxalylglycine
IC 50 (hTET2CDdel) 1, A = 149 M
IC 50 (NgTET1, FP) 3, C = 49 M
HO
O
O
O
OH
2OG, 3
2-oxoglutraric acid
K m (hTET2CDdel) 1, A = 15.7 M
K m (hTET3CDdel) 1, A = 24.2 M
K m (mTet1CD) 2, B = 55 M
K m (mTet2CD) 2, B = 60 M
IC 50 (NgTET1) 3, C = 250 M
HO
OH
O
OH
O
IC 50 (NgTET1) 3, C = 5.2 mM
IC 50 (hTET2CDdel) 1, A = 5.3 mM
%I (10 mM, mTet2CD)
4, D = 33%
%I (10 mM, mTet1CD)
4, D = 28%
IC 50 (mTet1CD) 2, B = 4 mM
IC 50 (mTet2CD) 2, B = 5 mM
HO
O
OH
O
IC 50 (hTET2CDdel) 1, A = 12.4 mM
%I (10 mM mTet2CD)
4, D = >90%
%I (10 mM mTet1CD)
4, D = >90%
IC 50 (mTet1CD) 2, B = 1 mM
IC 50 (mTet2CD) 2, B = 1.6 mM
OH
R-2HG (D-2HG), 28
R-2-hydroxyglutaric acid
L-2HG (S-2HG), 29
L-2-hydroxyglutaric acid
HO
O
O
OH
Succinate, 31
IC 50 (mTet1CD) 2, B = 540 M
IC 50 (mTet2CD) 2, B = 570 M
HO
O
O
OH
Fumarate, 32
IC 50 (mTet1CD) 2, B = 390 M
IC 50 (mTet2CD) 2, B = 400 M
O
OH
O
COONa
NH
H
N
S
N
OH
O
HOOC
7
NgTET1 fluorescent probe, 33
K d (hTET1CD) 6, E = 113 nM
IC 50 (hTET1CD) 5, E = 1.48 M
IC 50 (hTET2CD) 5, E > 10 M
K d (hTET1CD) 6, E = 116 nM
IC 50 (hTET1CD) 5, E = 1.13 M
IC 50 (hTET2CD) 5, E = 2.42 M
K d (hTET1CD) 6, E = 216 nM
IC 50 (hTET1CD) 5, E = 1.44 M
IC 50 (hTET2CD) 5, E = 1.62 M
Ac- D YLIYAYYTWWEHSC-NH 2
Ac- D YWYLPSYRVPWFC-NH 2
Ac- D YYRVKTYYQITYVYLSC-NH 2
S
S
S
N
OH
O
OH
O
2,4-PDCA, 35
2,4-pyridinedicarboxylic acid
N
O
OH
OH
IOX1, 34
8-hydroxyquinoline
K d (NgTET1) C = 250 nM
IC 50 (hTET1CD) 5, E = 1 M
IC 50 (hTET2CD, AS) 5, E = 0.7 M
IC 50 (NgTET1) 3, C = 27 M
TiP1, 36
TiP2, 37
TiP3M15L, 38
Fig. 8 Structures of TET inhibitors. Structures of the cofactor 2OG, TCA cycle intermediates and
metabolites and small molecules and cyclic peptides that bind to or inhibit the TET proteins are
shown. IC 50 , K d or percentage inhibition of activity (%I) are stated at tested concentration. Assay
methods used for affinity or inhibition are noted as superscript: (1) MALDI-TOF MS, (2)
14
CO 2
radiolabelling, (3) FP, (4) TLC, (5) AlphaScreen, (6) SPR. (A) Sudhamalla et al. [108], (B) Laukka
et al. [160], (C) Marholz et al. [163], (D) Xu et al. [159], (E) Nishio et al. [158]
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
275
contributory role in the tumorigenicity of IDH mutant cells. Other TCA cycle
intermediates, such as succinate (31) and fumarate (32), can also accumulate as a
result of tumour-associated mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) [168]. Biochemical assays using
HO
O
H
N
O
O
OH
NOG, 30
N-oxalylglycine
IC 50 (hTET2CDdel) 1, A = 149 M
IC 50 (NgTET1, FP) 3, C = 49 M
HO
O
O
O
OH
2OG, 3
2-oxoglutraric acid
K m (hTET2CDdel) 1, A = 15.7 M
K m (hTET3CDdel) 1, A = 24.2 M
K m (mTet1CD) 2, B = 55 M
K m (mTet2CD) 2, B = 60 M
IC 50 (NgTET1) 3, C = 250 M
HO
OH
O
OH
O
IC 50 (NgTET1) 3, C = 5.2 mM
IC 50 (hTET2CDdel) 1, A = 5.3 mM
%I (10 mM, mTet2CD)
4, D = 33%
%I (10 mM, mTet1CD)
4, D = 28%
IC 50 (mTet1CD) 2, B = 4 mM
IC 50 (mTet2CD) 2, B = 5 mM
HO
O
OH
O
IC 50 (hTET2CDdel) 1, A = 12.4 mM
%I (10 mM mTet2CD)
4, D = >90%
%I (10 mM mTet1CD)
4, D = >90%
IC 50 (mTet1CD) 2, B = 1 mM
IC 50 (mTet2CD) 2, B = 1.6 mM
OH
R-2HG (D-2HG), 28
R-2-hydroxyglutaric acid
L-2HG (S-2HG), 29
L-2-hydroxyglutaric acid
HO
O
O
OH
Succinate, 31
IC 50 (mTet1CD) 2, B = 540 M
IC 50 (mTet2CD) 2, B = 570 M
HO
O
O
OH
Fumarate, 32
IC 50 (mTet1CD) 2, B = 390 M
IC 50 (mTet2CD) 2, B = 400 M
O
OH
O
COONa
NH
H
N
S
N
OH
O
HOOC
7
NgTET1 fluorescent probe, 33
K d (hTET1CD) 6, E = 113 nM
IC 50 (hTET1CD) 5, E = 1.48 M
IC 50 (hTET2CD) 5, E > 10 M
K d (hTET1CD) 6, E = 116 nM
IC 50 (hTET1CD) 5, E = 1.13 M
IC 50 (hTET2CD) 5, E = 2.42 M
K d (hTET1CD) 6, E = 216 nM
IC 50 (hTET1CD) 5, E = 1.44 M
IC 50 (hTET2CD) 5, E = 1.62 M
Ac- D YLIYAYYTWWEHSC-NH 2
Ac- D YWYLPSYRVPWFC-NH 2
Ac- D YYRVKTYYQITYVYLSC-NH 2
S
S
S
N
OH
O
OH
O
2,4-PDCA, 35
2,4-pyridinedicarboxylic acid
N
O
OH
OH
IOX1, 34
8-hydroxyquinoline
K d (NgTET1) C = 250 nM
IC 50 (hTET1CD) 5, E = 1 M
IC 50 (hTET2CD, AS) 5, E = 0.7 M
IC 50 (NgTET1) 3, C = 27 M
TiP1, 36
TiP2, 37
TiP3M15L, 38
Fig. 8 Structures of TET inhibitors. Structures of the cofactor 2OG, TCA cycle intermediates and
metabolites and small molecules and cyclic peptides that bind to or inhibit the TET proteins are
shown. IC 50 , K d or percentage inhibition of activity (%I) are stated at tested concentration. Assay
methods used for affinity or inhibition are noted as superscript: (1) MALDI-TOF MS, (2)
14
CO 2
radiolabelling, (3) FP, (4) TLC, (5) AlphaScreen, (6) SPR. (A) Sudhamalla et al. [108], (B) Laukka
et al. [160], (C) Marholz et al. [163], (D) Xu et al. [159], (E) Nishio et al. [158]
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
275