AZD3759 hydrochloride

SKU: orb1303024

Description

AZD3759 hydrochloride is a brain-penetrant, orally bioavailable EGFR inhibitor with potent activity against mutant forms, including L858R and exon 19 deletion, as well as wild-type EGFR. It is a valuable research tool for investigating EGFR-driven cancers, particularly in models of brain metastasis, in both in vitro and in vivo studies.

Research Area

Cardiovascular Research, Cell Biology, Signal Transduction

Key Properties

• CAS Number: 1626387-81-2
• MW: 496.36
• Purity: 99.41%
• Formula: C₂₂H₂₄Cl₂FN₅O₃
• SMILES: C[C@@H]1CN(CCN1C(=O)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC)C.Cl
• Target: Apoptosis,EGFR
• Solubility: DMSO:50 mg/mL (100.73 mM)

Bioactivity

• Target IC50:
  EGFR (WT):0.3nM|EGFR (L858R):0.2nM|EGFR (exon 19Del):0.2 nM
• In Vivo:
  In rats, absorption of AZD3759 (2 mg/kg, p.o.) is rapid with blood Cmax of 0.58 μM achieved at 1.0 h. And then blood concentrations of AZD3759 decline monoexponentially with a mean elimination half-life of 4.3 h, which is close to the parameter obtained from intravenous dosing of 4.1 h. The bioavailability following an oral dose in rats is 91%. Following the intravenous in dogs, the blood clearance of AZD3759 is 14 mL/min/kg, and the volume of distribution is 6.4 L/kg. Its elimination half-life is 6.2 h. Absorption of AZD3759 is rapid with blood Cmax (698 nM) occurring between 0.5 and 1.5 h. The oral bioavailability of AZD3759 is excellent at 90%. AZD3759 demonstrated significant dose-dependent antitumor efficacy (78% tumor growth inhibition at 7.5 mg/kg/day and tumor regression at 15 mg/kg/day, respectively, 4 weeks after treatment) with <20% body weight loss. AZD3759 (7.5/15 mg/kg) can markedly decrease tumor area. In addition, modulation of pEGFR is detected by a single dose of AZD3759 at 15 mg/kg 1h after dosing.
• In Vitro:
  At 2 mM of ATP concentrations, the IC50s are 102/7.6/2.4 nM for EGFR (wt)/EGFR (L858R)/EGFR (exon 19Del). AZD3759 also inhibits pEGFR in H838wt (IC50: 64.5 nM), H3255L858R (IC50: 7.2 nM), and PC-9exon 19Del (IC50: 7.4 nM), respectively. In cellular phosphorylation studies, AZD3759 also shows 9-fold inhibition selectivity in EGFR-activating mutant cell lines over EGFR wild-type cell lines (H838 cell line).
• Cell Research:
  AZD3759 is prepared in DMSO and stored,and then diluted with the appropriate medium before use.Cell proliferation assay is determined by MTS methods.Briefly,cells are seeded in 96-well plates (at a density to allow for logarithmic growth during the 72-hour assay) and incubated overnight at 37°C and 5% CO2.Cells are then exposed to concentrations of compounds (e.g.,AZD3759) ranging from 30 mM to 0.3 μM for 72 hours.For the MTS endpoint,cell proliferation is measured by the CellTiter AQueous Non-Radioactive Cell Proliferation Assay reagent.Absorbance is measured with a Tecan Ultra instrument.Predose measurements are made,and concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) values are determined using absorbance readings.
• Animal Research:
  AZD3759 is prepared in 1% methylcellulose (Rat).Male Han Wistar rats are orally dosed with the AZD3759 at 2 mg/kg in 1% methylcellulose. At 0.25, 0.5, 1, 2, 4 and 7 hour post-dose, cerebral spinal fluid (CSF) is collected from cisterna magna, and blood samples (>60 μL/time point/each site) are collected via cardiac puncture, into separate EDTA coagulated tubes, and then immediately diluted with 3-fold volume of water. Brain tissue is harvested and homogenized in 3x volume of 100 mM phosphate buffered saline (pH7.4). All samples are stored at -70°C prior to LC/MS/MS analysis.

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

AZD3759 hydrochloride, AZD3759 Hydrochloride, AZD-3759 hydrochloride, AZD-3759 Hydrochloride, AZD 3759 Hydrochloride, EGFR (exon 19De), EGFR (L858R), EGFR (wt)

Compound Identifiers

PubChem CID

78322366