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Purity: ≥98%
BAY-1436032 is a novel and potent pan-mutant isocitrate dehydrogenase 1 (IDH1) inhibitor both in vitro and in vivo. Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
| ln Vitro |
BAY-1436032 is a brand-new pan-mutant inhibitor of isocitrate dehydrogenase 1 (IDH1). In mouse hematopoietic cells expressing IDH1R132H or IDH1R132C, BAY-1436032 reduces intracellular (R)-2-hydroxyglutarate (R-2HG) synthesis with IC50 values of 60 and 45 nM, respectively. Even at dosages up to 10 μM, BAY-1436032 does not lower R-2HG levels in mouse hematopoietic cells expressing IDH2R140Q and IDH2R172K. At doses as high as 100 μM, BAY-1436032 did not impede the colony expansion of patient-derived IDH1 wild-type AML cells, but it did at 50% when it came to that growth. BAY-1436032 significantly enhanced myelomonocytic differentiation of myeloid progenitor cells in morphological assessment [1].
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| ln Vivo |
At 150 mg/kg, long-term oral treatment of BAY-1436032 once daily showed nearly total suppression of (R)-2-hydroxyglutarate (R-2HG) synthesis. White blood cell counts in mice given vehicle treatment climbed steadily; in mice given 45 mg/kg BAY-1436032, the rate of increase was slowed; and in the 150 mg/kg group, the numbers were unchanged. Day 60 hemoglobin levels were marginally lower in the vehicle group and 45 mg/kg group than in the 150 mg/kg group, while the mice treated with BAY-1436032 at 45 mg/kg group and the vehicle group had marginally lower hemoglobin levels than the animals in the 150 mg group. Day 60 saw a significant reduction in the cohort's platelet count/kg. While animals treated with vehicles died, all mice given 150 mg/kg BAY-1436032 survived and had the lowest hCD45+ cell load in the peripheral blood until the end of observation on day 150 after the start of therapy (P<0.001). Bits have a 91-day lifespan. A 45 mg/kg dose of BAY-1436032 produced moderately expressed CD14/CD15 in mice [1].
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| References | |
| Additional Infomation |
Pan-Mutant-IDH1 Inhibitor Bay-1436032 is an orally available pan-inhibitor of mutant forms of the metabolic enzyme isocitrate dehydrogenase type 1 (IDH1; IDH-1; IDH1 [NADP+] soluble), including forms with mutations of arginine 132 (IDH1(R132)), with potential antineoplastic activity. Upon administration, pan-mutant-IDH-1 inhibitor BAY-1436032 specifically inhibits the activity of IDH1 mutant forms, which prevents the formation of the oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG). This prevents 2HG-mediated signaling and leads to both an induction of cellular differentiation and an inhibition of cellular proliferation in tumor cells expressing IDH1 mutant forms. IDH1 mutations, including IDH1(R132) mutations, are highly expressed in certain malignancies; they initiate and drive cancer growth by both blocking cell differentiation and catalyzing the formation of 2HG.
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| Molecular Formula |
C26H30F3N3O3
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|---|---|
| Molecular Weight |
489.529917240143
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| Exact Mass |
489.22
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| Elemental Analysis |
C, 63.79; H, 6.18; F, 11.64; N, 8.58; O, 9.80
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| CAS # |
1803274-65-8
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| PubChem CID |
118310260
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| Appearance |
White to gray solid powder
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| LogP |
7.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
726
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H]1C[C@H](CC(C1)(C)C)N2C3=C(C=C(C=C3)CCC(=O)O)N=C2NC4=CC=C(C=C4)OC(F)(F)F
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| InChi Key |
RNMAUIMMNAHKQR-QFBILLFUSA-N
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| InChi Code |
InChI=1S/C26H30F3N3O3/c1-16-12-19(15-25(2,3)14-16)32-22-10-4-17(5-11-23(33)34)13-21(22)31-24(32)30-18-6-8-20(9-7-18)35-26(27,28)29/h4,6-10,13,16,19H,5,11-12,14-15H2,1-3H3,(H,30,31)(H,33,34)/t16-,19+/m0/s1
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| Chemical Name |
3-(2-((4-(trifluoromethoxy)phenyl)amino)-1-((1R,5R)-3,3,5-trimethylcyclohexyl)-1H-benzo[d]imidazol-5-yl)propanoic acid
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| Synonyms |
BAY-1436032; BAY 1436032; BAY1436032.
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| HS Tariff Code |
2934.99.9001
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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 (~255.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.11 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 (5.11 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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: ≥ 2.5 mg/mL (5.11 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 | 2.0428 mL | 10.2139 mL | 20.4278 mL | |
| 5 mM | 0.4086 mL | 2.0428 mL | 4.0856 mL | |
| 10 mM | 0.2043 mL | 1.0214 mL | 2.0428 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.
BAY1436032 inhibits proliferation and induces myeloid differentiation in patient-derived IDH1 mutant AML cellsex vivo.Leukemia. 2017 Oct;31(10):2020-2028. |
BAY1436032 induces myeloid differentiation of IDH1R132C mutant AML cellsin vivo.Leukemia. 2017 Oct;31(10):2020-2028. |
BAY1436032 impacts on histone methylation in patient-derived IDH1R132C and IDH1R132H mutant AML cellsex vivo. |
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