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Purity: ≥98%
BAY-2402234 is a novel, potent/low-nanomolar and selective inhibitor of dihydroorotate dehydrogenase (DHODH) that has the potential for the treatment of myeloid malignancies. In vitro, BAY 2402234 potently inhibits proliferation of AML cell lines in the sub-nanomolar to low-nanomolar range. BAY 2402234 induces differentiation of AML cell lines also in a sub-nanomolar to low-nanomolar range, demonstrating the anticipated mode of action in cellular mechanistic assays. In vivo, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in several subcutaneous and disseminated AML xenografts as well as AML patient-derived xenograft (PDX) models. Target engagement of the novel DHODH inhibitor BAY 2402234 can be observed by increase of tumoral and plasma dihydroorotate levels after treatment with the inhibitor. Consistent with the in vitro data BAY 2402234 induces AML differentiation in vivo as detected by upregulation of differentiation cell surface markers in xenograft and PDX models after treatment with the inhibitor. Furthermore, differentiation-associated transcriptomic changes were evident following a single administration of BAY 2402234 in vivo. The start of clinical investigations of BAY 2402234 is planned for early 2018.
| ln Vitro |
The human DHODH enzyme is selectively and low nanomolarly inhibited by BAY-2402234. It successfully suppresses AML cell line proliferation in vitro in the subnanomolar to low nanomolar range. In cellular mechanistic studies, BAY-2402234 also causes AML cell line differentiation in the subnanomolar to low nanomolar range, indicating the anticipated mode of action [1].
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| ln Vivo |
Both patient-derived xenograft (PDX) models of AML and a number of subcutaneous and disseminated AML xenografts showed strong in vivo anti-tumor activity when BAY-2402234 was used as monotherapy. After receiving the new DHODH inhibitor BAY-2402234, tumor and plasma dihydroorotate levels rise, indicating the drug's on-target actions. The increase of differentiated cell surface markers in xenograft and PDX models after inhibitor therapy indicates that BAY-2402234 enhanced AML differentiation in vivo, which is consistent with in vitro results. Furthermore, following a single in vivo dose of BAY-2402234, differentiation-related transcriptome alterations were visible [1].
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| References |
[1]. Andreas Janzer, et al. Abstract DDT02-04: BAY 2402234: A novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of myeloid malignancies. AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL.
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| Molecular Formula |
C21H18CLF5N4O4
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|---|---|
| Molecular Weight |
520.8370
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| CAS # |
2225819-06-5
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| SMILES |
FC1=C(NC(C2=CC(F)=C(N3N=C(CO)N(CC)C3=O)C=C2O[C@@H](C)C(F)(F)F)=O)C(Cl)=CC=C1
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| InChi Key |
KNVJMHHAXCPZHF-JTQLQIEISA-N
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| InChi Code |
InChI=1S/C21H18ClF5N4O4/c1-3-30-17(9-32)29-31(20(30)34)15-8-16(35-10(2)21(25,26)27)11(7-14(15)24)19(33)28-18-12(22)5-4-6-13(18)23/h4-8,10,32H,3,9H2,1-2H3,(H,28,33)/t10-/m0/s1
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| Chemical Name |
(S)-N-(2-chloro-6-fluorophenyl)-4-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)benzamide
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| Synonyms |
BAY-2402234; BAY 2402234; BAY2402234
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| 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)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~240.00 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.99 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 20.8 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: ≥ 2.08 mg/mL (3.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9200 mL | 9.5999 mL | 19.1998 mL | |
| 5 mM | 0.3840 mL | 1.9200 mL | 3.8400 mL | |
| 10 mM | 0.1920 mL | 0.9600 mL | 1.9200 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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