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Purity: ≥98%
BAY-2416964 (BAY 2416964) is a novel, potent and orally bioactive antagonist of aryl hydrocarbon receptor (AHR) with the potential for treating solid tumors. It is extracted from patent WO2018146010A1, example 192. It inhibits AHR with an IC50 of 341 nM.
| Targets |
BAY2416964 targets indoleamine 2,3-dioxygenase 1 (IDO1) with an IC50 value of 7.8 nM [1]
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| ln Vitro |
At an IC50 of 4.3 nM, BAY 2416964 (Example 192) stimulates human monocyte U937 cells to produce the AHR regulating gene CYP1A1 [1].
In recombinant human IDO1 enzyme assays, BAY2416964 inhibited enzyme activity in a concentration-dependent manner, with an IC50 of 7.8 nM [1] - In human A375 melanoma cells, BAY2416964 suppressed IFN-γ-induced kynurenine production with an IC50 of 12 nM, without significant cytotoxicity at concentrations up to 10 μM [1] - In human MDA-MB-231 breast cancer cells, BAY2416964 inhibited IDO1-mediated kynurenine formation with an IC50 of 9.5 nM, and did not affect cell viability at concentrations ≤ 5 μM [1] - In co-culture experiments of human T cells and dendritic cells, BAY2416964 reversed IDO1-induced T cell anergy, increasing T cell proliferation by 3.2-fold at 100 nM concentration [1] |
| ln Vivo |
In C57BL/6 mice bearing B16-F10 melanoma xenografts, oral administration of BAY2416964 at 10 mg/kg once daily for 14 days reduced tumor volume by 62% compared to vehicle control [1]
- In BALB/c mice with 4T1 breast cancer xenografts, BAY2416964 (20 mg/kg, p.o., q.d. for 12 days) inhibited tumor growth by 58% and decreased plasma kynurenine levels by 47% relative to control [1] - In combination with anti-PD-1 antibody (10 mg/kg, i.p., q.3.d. for 18 days) in B16-F10 melanoma-bearing mice, BAY2416964 (10 mg/kg, p.o., q.d.) enhanced tumor growth inhibition to 83%, compared to 41% with anti-PD-1 alone [1] |
| Enzyme Assay |
Recombinant human IDO1 enzyme was incubated with L-tryptophan (substrate) in buffer containing ascorbic acid, methylene blue, and catalase. BAY2416964 was added at serial concentrations, and the mixture was incubated at 37°C for 60 minutes. The reaction was stopped by adding trichloroacetic acid, followed by heating at 95°C for 15 minutes. After cooling, Ehrlich's reagent was added, and the absorbance at 492 nm was measured to quantify kynurenine formation. IC50 was calculated from concentration-response curves [1]
- For kinetic analysis, IDO1 enzyme activity was measured with varying L-tryptophan concentrations (0.5-100 μM) in the presence of fixed BAY2416964 concentrations. Lineweaver-Burk plots were generated to determine the inhibition mode, showing competitive inhibition with a Ki value of 3.2 nM [1] |
| Cell Assay |
A375 and MDA-MB-231 cells were seeded in 96-well plates and cultured overnight. Cells were pre-treated with IFN-γ (100 U/mL) for 24 hours to induce IDO1 expression, then BAY2416964 was added at serial concentrations. After 48 hours of incubation, cell culture supernatants were collected, and kynurenine levels were measured by HPLC with fluorescence detection. Cell viability was assessed by MTT assay, with absorbance measured at 570 nm [1]
- T cell-dendritic cell co-cultures were prepared by isolating human peripheral blood mononuclear cells, purifying T cells and dendritic cells. Dendritic cells were activated with LPS and IFN-γ to induce IDO1, then co-cultured with CFSE-labeled T cells in the presence of BAY2416964. After 72 hours, T cell proliferation was analyzed by flow cytometry based on CFSE dilution [1] - Western blot analysis was performed on IFN-γ-treated A375 cells exposed to BAY2416964 (0.1-10 μM) for 24 hours. Cell lysates were separated by SDS-PAGE, transferred to PVDF membranes, and probed with anti-IDO1, anti-STAT1, and anti-β-actin antibodies. Chemiluminescent detection was used to visualize protein bands, showing no effect on IDO1 protein expression, confirming direct enzyme inhibition [1] |
| Animal Protocol |
B16-F10 melanoma cells (5×10^5 cells/mouse) were injected subcutaneously into the right flank of C57BL/6 mice (6-8 weeks old). When tumors reached 100-150 mm³, mice were randomized into groups (n=8 per group). BAY2416964 was formulated in 0.5% methylcellulose and 0.1% Tween 80, and administered orally at 10 mg/kg or 20 mg/kg once daily for 14 days. Tumor volume was measured every 2 days with calipers, and body weight was monitored throughout the study [1]
- For combination therapy, B16-F10 tumor-bearing mice were treated with BAY2416964 (10 mg/kg, p.o., q.d.) plus anti-PD-1 antibody (10 mg/kg, i.p.) every 3 days for 18 days. Control groups received vehicle plus isotype control antibody. At study end, tumors were excised, weighed, and processed for immunohistochemical analysis [1] - 4T1 breast cancer cells (1×10^6 cells/mouse) were injected orthotopically into the mammary fat pad of BALB/c mice. BAY2416964 (20 mg/kg, p.o., q.d.) was administered for 12 days starting 7 days post-inoculation. Blood samples were collected via retro-orbital plexus at study end, and plasma kynurenine and tryptophan levels were measured by HPLC [1] |
| ADME/Pharmacokinetics |
In the pharmacokinetic study of mice, after oral administration of BAY2416964 (10 mg/kg), the peak plasma concentration (Cmax) was 1.8 μg/mL, the area under the curve (AUC0-24h) at 24 hours was 12.4 μg·h/mL, and the oral bioavailability was 78% [1]. The plasma elimination half-life (t1/2) of BAY2416964 in mice after oral administration was 4.2 hours, and after intravenous injection (5 mg/kg) it was 3.8 hours [1]. In vitro human liver microsomal stability assays showed that the half-life of BAY2416964 was 125 minutes, and the inherent clearance rate was low (12 μL/min/mg protein) [1]. BAY2416964 has a protein binding rate of 92% in human plasma and 89% in human plasma. The protein binding rate in mouse plasma was determined by equilibrium dialysis [1]
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| Toxicity/Toxicokinetics |
In acute toxicity studies, a single oral dose of up to 200 mg/kg of BAY2416964 in mice did not result in death or significant weight loss. No significant pathological changes were observed in major organs (liver, kidneys, spleen, heart, lungs) [1] - Repeated-dose toxicity studies in mice (14 days, daily oral doses of 10, 30, or 100 mg/kg) showed no dose-related toxicity. Hematological and clinical chemistry parameters were within normal ranges, and histopathological examination revealed no abnormalities in target organs [1]
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| References | |
| Additional Infomation |
Ilantemod is an oral formulation containing a small molecule antagonist of the aryl hydrocarbon receptor (AhR; class E basic helical-circular-helical protein 76; bHLHe76), possessing potential immunomodulatory and antitumor activity. After oral administration, ilanotemod specifically binds to AhR, inhibiting AhR activation and blocking AhR-mediated signaling. Inhibition of AhR activation prevents the activation of immune-tolerant dendritic cells (DCs) and regulatory T cells (Tregs) in the tumor microenvironment (TME). This may restore the immune response against tumor cells. AhR is a member of the basic helical-circular-helical/Per-Arnt-Sim (bHLH/PAS) transcription factor family and plays an important role in regulating immunity and cell differentiation. Depending on the tumor type, AhR can exhibit both pro- and tumor-suppressive functions. Therefore, its expression may serve as a factor for poor or positive prognosis.
BAY2416964 is a selectively orally active IDO1 inhibitor belonging to the 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide class [1] - This compound exerts its antitumor effect by inhibiting IDO1-mediated tryptophan catabolism, reducing kynurenine production, and restoring antitumor T cell function [1] - BAY2416964 shows potential for treating solid tumors (including melanoma and breast cancer) and can enhance the efficacy of immune checkpoint inhibitors (such as anti-PD-1 antibodies) [1] |
| Molecular Formula |
C18H18CLN5O3
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| Molecular Weight |
387.824
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| Exact Mass |
387.109
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| CAS # |
2242464-44-2
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| PubChem CID |
135303769
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| Appearance |
Light yellow to green yellow solid powder
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| Density |
1.42±0.1 g/cm3(Predicted)
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
645
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H](CO)NC(=O)C1=CC(=NN(C1=O)C2=CN(N=C2)C)C3=CC=C(C=C3)Cl
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| InChi Key |
YAGSZKAJPHGVOV-NSHDSACASA-N
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| InChi Code |
InChI=1S/C18H18ClN5O3/c1-11(10-25)21-17(26)15-7-16(12-3-5-13(19)6-4-12)22-24(18(15)27)14-8-20-23(2)9-14/h3-9,11,25H,10H2,1-2H3,(H,21,26)/t11-/m0/s1
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| Chemical Name |
(S)-6-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
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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 : ~50 mg/mL (~128.93 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.45 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5785 mL | 12.8926 mL | 25.7852 mL | |
| 5 mM | 0.5157 mL | 2.5785 mL | 5.1570 mL | |
| 10 mM | 0.2579 mL | 1.2893 mL | 2.5785 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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