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AZD 3759

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AZD-3759 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.

Product Description

Basic Characteristics

Product Name AZD 3759
CAS Number 1626387-80-1
Molecular Formula C22H23ClFN5O3
Formula Weight 459.90
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 (Free Acid/Base)Parameters.

Appearance crystalline powder
Storage and Handling Store under 20°C and protect from air and light, ≥ 2 years

 

AZD 3759 Description

AZD 3759 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 and exon 19 deletion-containing H3255 and PC-9 cells (GI50s = 7.7 and 7.0 nM, respectively) but has no effect on H838 cells that express wild-type EGFR (GI50 = 21,556 nM). AZD 3759 inhibits tumor growth by 78% and induces tumor regression at doses of 7.5 and 15 mg/kg, p.o., respectively in a PC-9 mouse model of non-small cell lung cancer (NSCLC) brain metastasis.

 

AZD 3759 Mechanism of Action

AZD-3759 is a potent epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. AZD-3759 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 Application

AZD-3759 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 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 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 Side Effects & Warning

AZD 3759 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

[1] 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.

[2] 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.

[3] 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.

[4] 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.

[5] 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.

[6] 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.