1448671-31-5

Basic information

• Product Name: AZD3965
• Synonyms: 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;(S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
• CAS NO: 1448671-31-5
• Molecular Formula: C21H24F3N5O5S
• Molecular Weight: 515.5059696
• Mol File: 1448671-31-5.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 723.1±70.0 °C(Predicted)
• Appearance: /
• Density: 1.483±0.06 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥51.5 mg/mL in DMSO; ≥51.6 mg/mL in EtOH
• PKA: 10.92±0.50(Predicted)
• CAS DataBase Reference: AZD3965(CAS DataBase Reference)
• NIST Chemistry Reference: AZD3965(1448671-31-5)
• EPA Substance Registry System: AZD3965(1448671-31-5)

Safety Data

• Hazardous Substances Data: 1448671-31-5(Hazardous Substances Data)

Usage

Description

AZD3965 is a potent inhibitor of monocarboxylate transporter 1 (MCT1), specifically designed to target and kill tumor cells that rely on glycolysis by blocking lactate transport. It exhibits a high binding affinity of 1.6 nM and demonstrates six-fold selectivity for MCT1 over MCT2, with no effect on MCT4 at 10 μM. This selective inhibition leads to increased intratumor lactate levels and reduced tumor growth, making AZD3965 a promising candidate for cancer treatment.

Uses

Used in Oncology:
AZD3965 is used as an anticancer agent for targeting tumor cells that depend on glycolysis. By inhibiting MCT1, it blocks lactate transport, leading to increased intratumor lactate levels and a subsequent decrease in tumor growth. This makes AZD3965 particularly effective against small cell lung cancer (SCLC) xenografts.
Additionally, AZD3965 is used to enhance radiosensitivity in mice with SCLC xenografts, improving the effectiveness of radiation therapy in treating cancer.
Used in Drug Development:
AZD3965 serves as a valuable compound in the development of novel cancer treatments. Its potent and selective inhibition of MCT1 makes it a promising candidate for further research and development, potentially leading to the creation of new therapies for various types of cancer.
Used in Preclinical Research:
AZD3965 is used as a research tool in preclinical studies to investigate the role of MCT1 in cancer progression and to explore the potential of MCT1 inhibition as a therapeutic strategy. Its selectivity and potency make it an ideal candidate for studying the effects of MCT1 inhibition on tumor growth and response to other cancer treatments.

In vivo

In nonobese diabetic scid-γ mice bearing COR-L103 xenografts, AZD3965 (100 mg/kg, p.o.) reduces tumor growth and increased intratumor lactate. In mice bearing H526 tumors, AZD3965 (100 mg/kg, p.o.) causes increased lactate concentration, a reduction in growth and increased radiation sensitivity.

In vitro

In lymphoma cell lines that preferentially express MCT1, AZD3965 potently inhibits lactate transport and cell growth. AZD3965 inhibits MCT1 activity in cells, and shows higher sensitivity in hypoxia.? In H526, HGC27 cells and DMS114 cells, AZD3965 increases intracellular lactate and significantly reduces lactate uptake.

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].

Enzyme inhibitor

This orally bioavailable MCT1 inhibitor (FW = 515.51 g/mol; CASs = 733809-45-5 and 1448671-31-5), also named (S) -5- (4-hydroxy-4- methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- ( (3-methyl-5- (tri- fluoromethyl) -1H-pyrazol-4-yl) methyl) -thieno[2,3-d]pyrimidine-2,4 (1H, 3H) -dione, selectively targets the Monocarboxylate Transporter-1 (IC50 = 1.6 nM) and is ~6x less active toward MCT2. AZD3965 does not inhibit MCT4, even at 10 μM. MCT1 and MCT4 are primarily involved in lactate transport, targeting highly glycolytic cancer cells, especially those that are hypoxic. The latter property suggests that the combined use with a vascular-disrupting anticancer agent (such as combrestatin) may improve the inhibitory action of AZD-3965 against cancer cells.

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

Upstream product

• 733810-92-9 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-6-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid 

Relevant articles and documents

THIENOPYRIMIDINEDIONES AND THEIR USE IN THE MODULATION OF AUTOIMMUNE DISEASE

The invention relates to thienopyrimidinediones of formula (1) wherein R1 and R2 each independently represent a C1-6akyl, C3-6alkyl, C3-6alkenyl, C3-5cycloalkylC1-3alkyl or Csub