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Purity: ≥98%
AZD3965 is a novel, potent and selective MCT1 (monocarboxylate transporter 1) inhibitor with a Ki of 1.6 nM, it showed 6-fold selectivity over MCT2. Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. The combination of AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors.
| ln Vitro |
The purpose of AZD3965 is to obstruct single-effector transporter-1 (MCT1), which is anticipated to impact cell entry and exit [1]. The administration of AZD3965 led to an increase in internal repletion of 3.7 times in hypoxic COR-L103 cells and 3.9 times in normoxic and hypoxic NCI-H1048 cells, respectively. A <1.9-fold rise was noted in all other cases. These results are in line with the theory that AZD3965 both decreases the number of cells and blocks leaky movement in cells. The EC50 of NCI-H1048 rises from 0.14 nM to 10.5 nM in NCI-H1048 cells when MCT1 is overexpressed, which is consistent with AZD3965's inhibitory impact via MCT1 [2].
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| ln Vivo |
Tumor volume was tracked while AZD3965 (100 mg/kg) or vehicle BID was administered for 21 days to COR-L103 tumor-bearing mutants. According to pharmacokinetic research, AZD3965 at a dose of 100 mg/kg produced free quantities of the drug that were expected to prevent exchange transit. Because AZD3965 only inhibits the hypoxic portion of the tumor, treatment with it considerably slowed the growth of COR-L103 tumors but did not cause any tumor regression [2].
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| References |
[1]. Bola BM, et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. Mol Cancer Ther. 2014 Dec;13(12):2805-16.
[2]. Polanski R, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014 Feb 15;20(4):926-37 |
| Molecular Formula |
C21H24F3N5O5S
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|---|---|
| Molecular Weight |
515.5060
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| CAS # |
1448671-31-5
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| Related CAS # |
1448671-31-5; 733809-45-5;
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| SMILES |
O=C1N(C(C)C)C2=C(C(C(N3OC[C@@](C)(O)C3)=O)=C(CC4=C(C(F)(F)F)NN=C4C)S2)C(N1C)=O.
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| InChi Key |
PRNXOFBDXNTIFG-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C21H24F3N5O5S/c1-9(2)29-18-14(16(30)27(5)19(29)32)13(17(31)28-7-20(4,33)8-34-28)12(35-18)6-11-10(3)25-26-15(11)21(22,23)24/h9,33H,6-8H2,1-5H3,(H,25,26)/t20-/m0/s1
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| Chemical Name |
(S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
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| Synonyms |
AZD3965; AZD-3965; AZD 3965
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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 : ~100 mg/mL (~193.98 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.03 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 (4.03 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 (4.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5 mg/mL (9.70 mM) in 20% HP-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<60°C). Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 5 mg/mL (9.70 mM) in 0.5% HPMC 0.2%Tween80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9398 mL | 9.6991 mL | 19.3983 mL | |
| 5 mM | 0.3880 mL | 1.9398 mL | 3.8797 mL | |
| 10 mM | 0.1940 mL | 0.9699 mL | 1.9398 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.
Effect of AZD3965 on lactate concentration, blood vessel density and MCT4 expression in H526 xenografts.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
AZD3965 increases intracellular lactate whilst decreasing the amount of extracellular lactate.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
AZD3965 significantly reduces lactate uptake.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
Inhibiting lactate transport increases glycolytic rate.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
Combining AZD3965 with radiation to treat H526 xenografts.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
AZD3965 slows H526 xenograft growthin vivo.A)In vivogrowth curves showing tumour volume (mean and SEM) in mm3post start of treatment; the growth curve finishes when the first tumour in each group reaches 1000mm3. The control group contained 5 mice the AZD3965 group contained 11 mice three of which were sacrificed for histology at the end of drug treatment (day 7).B) Days (±SEM) taken to reach 1000mm3for each treatment group
The effect of inhibiting lactate transport on metabolism.Mol Cancer Ther. 2014 Dec;13(12):2805-16. |
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