Table 2.
Inhibitors targeting IDH1 in the preclinical study stage.
| Compound | Structure | In vitro activity | In vivo activity/PK/ADME | Ref. |
|---|---|---|---|---|
| AGI-5198 |  |
IDH1R132H (enzyme): IC50 = 0.07 μmol/L; U87 (cell lines): IC50 = 0.07 μmol/L |
U87 R132H tumor xenograft mouse model: 2-HG inhibition: 89.4% (BID) and 69% (Single) |
158 |
| ML309 |  |
IDH1R132H (enzyme): IC50 = 96 nmol/L; U87 MG cells: 2-HG assay: EC50 = 509 nmol/L |
Male BALB/c nude mice: Tmax = 1.0 h; Cmax = 3625 ng/mL; t1/2 = 3.76 h |
160 |
| (R)-1-(4-Cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide (6f) |  |
IDH1R132H (enzyme): IC50 = 45 nmol/L; IDH1R132C HT-1080 cells: 2-HG inhibition: IC50 < 5 nmol/L |
– | 161 |
| IDH-C227 |  |
IC50 < 0.1 μmol/L against HT-1080 and 0.25 μmol/L against U87MG cells. | – | 187 |
| N-(2-(Cyclohexylamino)-1-(4-methoxy-2-methylphenyl)-2-oxoethyl)-N-(4-nitrophenyl)propiolamide (43) |  |
IDH1R132H (enzyme): IC50 = 961.5 nmol/L IDH1R132H U87 cells 2-HG inhibition: EC50 = 208.6 nmol/L |
– | 162 |
| IDH125 |  |
IDH1R132H (enzyme): IC50 = 0.22 μmol/L; IDH1R132H HCT116 cells 2-HG inhibition: IC50 = 0.66 μmol/L |
– | 163 |
| IDH662 |  |
IDH1R132H (enzyme): IC50 = 0.01 μmol/L; IDH1R132H HCT116 cells 2-HG inhibition: IC50 = 0.022 μmol/L |
Plasma protein binding >99% |
163 |
| IDH889 |  |
IDH1R132H (enzyme): IC50 = 0.02 μmol/L; IDH1R132H HCT116 cells: 2-HG inhibition: IC50 = 0.014 μmol/L |
HCT116 R132H tumor xenograft mouse model (10 mg/kg, Oral) AUC: 3.6 μmol/(L·h), Cmax: 1.7 μmol/L Brain/plasma ratio: 1.4 |
163 |
| NI-1 |  |
IDH1R132H (enzyme): IC50 = 96 nmol/L |
– | 166 |
| (R)-4-(Fluoromethyl)-3-(2-(((S)-1-(1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (19) |  |
IDH1R132H HCT116 cells: 2-HG inhibition: IC50 = 0.039 μmol/L |
Rat liver microsomal (10 mg/kg, Oral) Clint: 7 μL/min/mg AUC: 180 μmol/(L‧h) |
164 |
| (R)-3-(2-((1-(1-(3-Chloro-4-fluorophenyl)-1H-imidazole-4-yl)cyclopropyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one (5t) |  |
IDH1R132H (enzyme): IC50 = 35 nmol/L; IDH1R132H HT-1080 cells 2-HG inhibition: IC50 = 18 nmol/L |
Rat liver microsomal: Clint: 45 mL/min/g |
165 |
| (S)-4-Isopropyl-3-(6-(((S)-1-(2′-methoxy-[1,1′-biphenyl]-4-yl)ethyl)amino)pyrazin-2-yl)oxazolidin-2-one (3g) |  |
2-HG levels (%, IDH1 R132H): 31.9% (10 μmol/L) 2-HG levels (%, IDH1 R132C): 40.6% (10 μmol/L) |
PAMPA-BBB assaya: Permeability (×10−6 cm/s): 6.65 ± 0.42 |
166 |
| I-8 |  |
IDH1R132H (enzyme): IC50 = 135.6 ± 17.9 nmol/L IDH1R132C (enzyme): IC50 = 174.2 ± 22.1 μmol/L |
HT-1080 R132C tumor xenograft BALB/c mice 150 mg/kg could induce 30% inhibitory of 2-HG production |
167 |
| IDH1-IN-6 |  |
IDH1R132H (enzyme): IC50 = 6.27 nmol/L; IDH1R132C (enzyme): IC50 = 36.9 nmol/L; IDH1R132C HT-1080 cells: 2-HG inhibition: IC50 = 1.28 nmol/L |
– | 168 |
| SYC-435 (Compound 2) |  |
IDH1R132H (enzyme): Ki = 0.19 μmol/L; IDH1R132C (enzyme): Ki = 0.12 μmol/L |
– | 169 |
| 1-Hydroxy-6-(4-hydroxybenzyl)-4-methylpyridin-2(1H)-one (3) |  |
IDH1R132H (enzyme): Ki = 0.28 μmol/L; IDH1R132C (enzyme): Ki = 0.27 μmol/L |
– | 169 |
| Thiohydantoin16 (16) |  |
IDH1R132H (enzyme): Ki = 0.75 μmol/L; IDH1R132C (enzyme): Ki = 1.2 μmol/L |
– | 171 |
| (E)-5-((5-oxo-2-Thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one (18) |  |
IDH1R132H (enzyme): Ki = 0.42 μmol/L; IDH1R132C (enzyme): Ki = 2.3 μmol/L |
– | 171 |
| GSK321 |  |
HT-1080 cells: 2-HG inhibition: EC50 = 85 nmol/L; IDH1R132H (enzyme): IC50 = 4.6 nmol/L; IDH1R132C (enzyme): IC50 = 3.9 nmol/L; IDH1R132G (enzyme): IC50 = 2.9 nmol/L |
2-HG inhibition: (IDH1R132C HT-1080 fibrosarcoma cells): EC50 = 320 nmol/L |
172 |
| GSK864 |  |
IDH1R132H (enzyme): IC50 = 15.2 nmol/L; IDH1R132C (enzyme): IC50 = 8.8 nmol/L; IDH1R132G (enzyme): IC50 = 16.6 nmol/L |
– | 172 |
| (6aS,7S,10aR)-7-Methyl-8-oxo-10a-phenyl-2-(phenylamino)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile (1) |  |
IDH1WT (enzyme): IC50 = 410 nmol/L |
– | 172 |
| BRD2879 |  |
IDH1R132H (enzyme): IC50 = 50 nmol/L; IDH1R132C (enzyme): IC50 = 2.5 μmol/L |
Human plasma protein binding: 99.5% | 173 |
| (S)-2-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-4-methoxypyrimidine-5-carbonitrile (63) |  |
IDH1R132H (enzyme): IC50 = 18 nmol/L; IDH1R132C (enzyme): IC50 = 130 nmol/L; IDH1R132H HCT116 cells: 2-HG inhibition: IC50 = 45 nmol/L; IDH1R132C HCT116 cells: 2-HG inhibition: IC50 = 233 nmol/L |
HCT116 R132H/R132C xenograft bearing female BALB/c nude mice: 2-HG inhibition: IC50 = 49 nmol/L (R132H); IC50 = 46 nmol/L (R132C). |
174 |
| Bisimidazole 3 |  |
IDH1R132H (enzyme): IC50 = 13 ± 5 nmol/L; IDH1R132H HEK-293 cells: 2-HG inhibition: IC50 = 81.5 nmol/L |
– | 175 |
| 3-(1-(3-(1H-Imidazole-1-yl)propyl)-6-chloroindolin-3-yl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione (11e) |  |
IDH1R132H (enzyme): IC50 = 0.16 ± 0.04 μmol/L |
– | 176 |
| Licochalcone A |  |
IDH1R132H (enzyme): IC50 = 76.87 μmol/L; IDH1R132C (enzyme): IC50 = 5.176 μmol/L |
– | 165 |
| CRUK-MI 20a (20a) |  |
IDH1WT (enzyme): IC50 = 0.27 ± 0.22 μmol/L |
– | 177 |
| HMS-101 |  |
IDH1R132H (enzyme): IC50 = 5 μmol/L; IDH1R132C (enzyme): IC50 = 4 μmol/L |
– | 178 |
| Clomifene |  |
IDH1R132H (enzyme): IC50 = 50.20 ± 0.12 μmol/L; IDH1R132C (enzyme): IC50 = 42.33 ± 0.31 μmol/L; IDH1R132H HT-1080 cells: 2-HG inhibition: IC50 = 37.86 ± 0.32 μmol/L |
HT-1080 R132H tumor xenograft mouse model: 100 mg/kg Clomifene could induce 57.38% inhibitory of D-2HG production. |
179 |
| ZX06 |  |
2-HG levels (%, IDH1 R132H): 54.9% (10 μmol/L); 2-HG levels (%, IDH1 R132C): 48.4% (10 μmol/L) |
PAMPA-BBB assay: Permeability (×10−6 cm/s): 8.15 ± 0.29 |
180 |
| DC_H31 |  |
IDH1R132H (enzyme): IC50 = 0.41 μmol/L; IDH1R132C (enzyme): IC50 = 2.7 μmol/L |
– | 181 |
| KRC-09 |  |
IDH1R132H (enzyme): IC50 = 76.87 μmol/L; 2-HG levels: (IDH1 R132H): 45% (50 μmol/L) |
– | 182 |
| α-Mangostin |  |
IDH1R132H (enzyme): Ki = 2.85 μmol/L |
– | 183 |
| (8R,10R,13R)-17-((2R,5R,E)-5,6-Dimethylhept-3-en-2-yl)-8-hydroxy-10,13-dimethyl-1,2,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (3) |  |
IDH1R132H HT-1080 cells: 2-HG inhibition: IC50 = 35.97 μmol/L |
– | 184 |
| DOA |  |
IDH1R132H (enzyme): IC50 = 12 μmol/L |
– | 185 |
a
PAMPA-BBB: blood–brain barrier specific parallel artificial membrane permeability assay.