IDH-305 (IDH 305; IDH305) is a novel and potent inhibitor of isocitrate dehydrogenase 1 (IDH1) which is a citric acid cycle enzyme isocitrate dehydrogenase with potential antineoplastic activity.
Physicochemical Properties
| Molecular Formula | C23H22F4N6O2 |
| Molecular Weight | 490.453398227692 |
| Exact Mass | 490.174 |
| CAS # | 1628805-46-8 |
| PubChem CID | 90415637 |
| Appearance | White to off-white solid powder |
| LogP | 3.9 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 35 |
| Complexity | 731 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | F[C@@H](C)[C@H]1COC(N1C1C=CN=C(N[C@@H](C)C2C=C(C)C(C3C=CN=C(C(F)(F)F)C=3)=CN=2)N=1)=O |
| InChi Key | DCGDPJCUIKLTDU-SUNYJGFJSA-N |
| InChi Code | InChI=1S/C23H22F4N6O2/c1-12-8-17(30-10-16(12)15-4-6-28-19(9-15)23(25,26)27)14(3)31-21-29-7-5-20(32-21)33-18(13(2)24)11-35-22(33)34/h4-10,13-14,18H,11H2,1-3H3,(H,29,31,32)/t13-,14-,18+/m0/s1 |
| Chemical Name | (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2'-(trifluoromethyl)-[3,4'-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one |
| Synonyms | IDH305 IDH-305 IDH 305 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | HCT116-IDH1R132H+/- cells are inhibited by IDH-305 with an IC50 of 24 nM[1]. |
| ln Vivo | In the IDH1 mutant PDX melanoma model, IDH-305 (30-300 mg/kg; route; twice daily for 21 days) suppresses 2-HG production and 2-HG increases tumor growth [1]. |
| Animal Protocol |
Animal/Disease Models: nu /nu (nude) mice (HMEX2838-IDH1R132C+/-PDX model) [1] Doses: 30, 100, 300 mg/kg Route of Administration: po (oral gavage); twice a day for 21 days Experimental Results: 100 mg/ kg, 2-HG was diminished by 62-67%, showing significant anti-tumor activity; at 300 mg/kg, 2-HG was diminished by 97-99%, and some tumors were diminished by 32%. |
| References |
[1]. Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor. ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121. [2]. A Phase I Study of IDH305 in Patients with Advanced Malignancies Including Relapsed/Refractory AML and MDS That Harbor IDH1R132 Mutations. Blood, 128(22), 1073. |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 150 mg/mL (~305.84 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0389 mL | 10.1947 mL | 20.3894 mL | |
| 5 mM | 0.4078 mL | 2.0389 mL | 4.0779 mL | |
| 10 mM | 0.2039 mL | 1.0195 mL | 2.0389 mL |