AZD 3965
Ki = 1.6 nM for MCT1
AZD 3965 is a potent inhibitor of monocarboxylate transporter 1 (MCT1).
Inhibition of monocarboxylate transporter 1 (MCT1) is currently considered as a promosing therapeutic way to block lactate shuttling in tumor cells lacking monocarboxylate transporter 4.
In vitro: Previous study found that the in-vitro AZD3965 sensitivity varied and was highest in hypoxia. To further support that AZD3965 targeted MCT1, NCIH1048 cells were engineered to inducibly overexpress MCT1. It was found that when MCT1 was overexpressed, the EC50 of AZD 3965 against NCI-H1048 was increased from 0.14 to 10.5 nM, which was consistent with AZD3965 acting through MCT1 inhibition [1].
In vivo: COR-L103 xenograft studies were conducted to test whether the in-vitro effect of AZD3965 could be recapitulated in vivo. COR-L103 tumor-bearing mice were treated with AZD3965 at 100 mg/kg BID for 21 days. The pharmacokinetic analyses showed that AZD3965 at 100 mg/kg BID led to free concentrations of AZD3965 predicted to inhibit lactate transport. Moreover, AZD3965 treatment was able to reduce the growth of CORL103 tumors significantly, though tumor regression was not observed, which was consistent with AZD3965 only targeting the hypoxic fraction of the tumor [1].
Clinical trial: A phase I trial of AZD3965 in patients with advanced cancer is currently recruiting participants [2].
References:
[1] Polanski, R. ,Hodgkinson, C.L.,Fusi, A., et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin.Cancer.Res 20(4), (2014).
[2] https://clinicaltrials. gov/ct2/show/NCT01791595 term=AZD+3965&rank=1
| Storage | Store at -20°C |
| M.Wt | 515.5 |
| Cas No. | 1448671-31-5 |
| Formula | C21H24F3N5O5S |
| Solubility | insoluble in H2O; ≥51.5 mg/mL in DMSO; ≥51.6 mg/mL in EtOH |
| Chemical Name | 5-[[(4S)-4-hydroxy-4-methyl-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)-6-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione |
| SDF | Download SDF |
| Canonical SMILES | CC(C)N(C(N1C)=O)C2=C(C(C(N3C[C@](C)(O)CO3)=O)=C(CC4=C(C)NN=C4C(F)(F)F)S2)C1=O |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment:[1] | |
|
Cell lines |
Small cell lung cancer (SCLC) cell lines, including COR-L103, NCI-H526, NCI-H1048, NCI-H524, DMS114, DMS79, and NCI-H146 |
|
Reaction Conditions |
8 nmol/L AZD 3965 for 72 h incubation |
|
Applications |
Cells cultured under hypoxic conditions were more sensitive to AZD 3965 than their normoxic counterparts. There was a wide range of responses of hypoxic cells to AZD 3965, with COR-L103, NCI-H526, and NCI-H1048 being relatively sensitive and DMS114, DMS79, and NCI-H146 relatively resistant. AZD 3965 sensitivity varied in vitro and was highest in hypoxia. |
| Animal experiment:[1] | |
|
Animal models |
Nonobese diabetic scid-γ mice bearing COR-L103 xenografts |
|
Dosage form |
100 mg/kg Twice daily by oral gavage for 21 days |
|
Applications |
AZD 3965 treatment significantly reduced the growth of COR-L103 tumors. Analysis of lactate concentration at sacrifice confirmed that the reduced tumor growth rate was accompanied by a significant increase in intratumor lactate. |
|
Note |
The technical data provided above is for reference only. |
|
References: 1. Polański R, Hodgkinson CL, Fusi A, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clinical Cancer Research, 2014, 20(4): 926-937. |
|
Quality Control & MSDS
- View current batch:
Chemical structure
