|Product Name||AZD 3759 powder|
|Synonyms||(2R)-2,4-dimethyl-1-piperazinecarboxylic acid, 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl ester; |
1-Piperazinecarboxylic acid, 2,4-dimethyl-, 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl ester, (2R)-AZD-3759 powder（Free Acid/Base）Parameters.
|Storage and Handling||Store under 20°C and protect from air and light, ≥ 2 years|
AZD 3759 Powder Description
AZD 3759 powder is a brain penetrant inhibitor of wild-type and constitutively active mutant EGF receptors (EGFRs; IC50s = 0.3, 0.2, and 0.2 nM for wild-type, L858R-mutant, and exon 19 deletion-containing EGFRs, respectively).It is selective for EGFR over 115 other kinases, exhibiting <50% inhibition at a concentration of 1 μm. azd 3579 reduces egfr phosphorylation and cellular proliferation in l858r-mutant exon 19 deletion-containing h3255 pc-9 cells (gi50s=7.7 7.0 nm, respectively) but has no effect on h838 that express wild-type (gi50=21,556 nm). 3759 powder inhibits tumor growth by 78% induces regression doses 7.5 15 mg/kg, p.o., respectively mouse model non-small cell lung cancer (nsclc) brain metastasis.
AZD 3759 Powder Mechanism of Action
AZD-3759 powder is a potent epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. AZD-3759 powder binds to and inhibits the activity of EGFR as well as certain mutant forms of EGFR. This prevents EGFR-mediated signaling, and may lead to both induction of cell death and inhibition of tumor growth in EGFR-overexpressing cells.
AZD 3759 Powder Application
AZD-3759 powder is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 powder can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 powder is currently in Phase 1 clinical trial.
♦ In vitro
In H3255 (L858R) cells, AZD3759 inhibits EGFR phosphorylation with IC50 of 7.2 nM. AZD3759 demonstrates inhibitory effects on both the pEGFR pathway and cell proliferation of EGFR mutation-derived cells PC-9 and H3255 with IC50 of 7.7 nM and 7 nM, respectively, showing mo activity on cell proliferation of H838 cells.
♦ In vivo
AZD3759 shows good oral bioavailability in dogs, and penetrates extensively into monkey brain. In a brain metastasis PC-9 (Exon19Del) model, AZD3759 (15 mg/kg) causes significant dose-dependent antitumor efficacy.
AZD 3759 Powder Side Effects & Warning
AZD 3759 powder is a type of EGFR inhibitors, Chemotherapy using EGFR or FGFR inhibitors can cause corneal epithelial changes with decreased visual acuity that recovers following discontinuation of the agents. Unfortunately, some physicians remain unaware of such side effects, leaving many patients unmanaged. Therefore, ophthalmologists should forewarn patients who are planning chemotherapy with such agents about the possibility of corneal changes that lead to the clouding of vision. Doctors should also clarify that the corneal lesions will probably resolve after the end of chemotherapy.
Reference Zeng Q, et al. Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem. 2015 Oct 22;58(20):8200-15.  Wang S, Zhou Y, Geng P, Zhang Q, Wen C. Pharmacokinetic interaction study between imatinib with sorafenib in rats. Lat Am J Pharm 2014; 33: 1723–7.  Chen DX, Geng PW, Zhang LJ et al Pharmacokinetic study of duloxetine in rat by liquid chromatography mass spectrometry. Lat Am J Pharm 2015; 34: 2078–83.  Zhou Y, Wang S, Geng P, Zhang Q, Ma J. Pharmacokinetic interaction between lapatinib and sorafenib following single and co‐oral administration in rats. Lat Am J Pharm 2014; 33: 1718–22.  Li X, Wang Y, Wang J et al Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non‐small cell lung cancer. Int J Cancer 2018; 143: 212–24.  Yang Z, Guo Q, Wang Y et al AZD3759, a BBB‐penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci Transl Med 2016; 8: 368ra172.