WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206182
Description: AZD3759 is also known as zorifertinib. It is an orally available inhibitor of the epidermal growth factor receptor (EGFR), with potential antineoplastic activity. Upon oral administration, AZD3759 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. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
MedKoo Cat#: 206182
Chemical Formula: C22H23ClFN5O3
Exact Mass: 459.14735
Molecular Weight: 459.91
Elemental Analysis: C, 57.46; H, 5.04; Cl, 7.71; F, 4.13; N, 15.23; O, 10.44
Related CAS #: 1626387-81-2 (HCl)
Synonym: AZD3759; AZD-3759; AZD 3759; zorifertinibum; zorifertinib.
IUPAC/Chemical Name: (R)-4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine-1-carboxylate
InChi Key: MXDSJQHFFDGFDK-CYBMUJFWSA-N
InChi Code: InChI=1S/C22H23ClFN5O3/c1-13-11-28(2)7-8-29(13)22(30)32-19-9-14-17(10-18(19)31-3)25-12-26-21(14)27-16-6-4-5-15(23)20(16)24/h4-6,9-10,12-13H,7-8,11H2,1-3H3,(H,25,26,27)/t13-/m1/s1
SMILES Code: O=C(N1[C@H](C)CN(C)CC1)OC2=CC3=C(NC4=CC=CC(Cl)=C4F)N=CN=C3C=C2OC
Appearance: white to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||AZD3759 inhibits EGFR. At Km ATP concentrations, the IC50s are 0.3, 0.2, and 0.2 nM for EGFRwt, EGFRL858R, and EGFRexon 19Del, respectively.|
|In vitro activity:||First, the effect of radiation and AZD3759 on cell proliferation in NSCLC cell lines expressing either wild type (WT) (H2228 and H226) or mutant EGFR (H3255 and PC-9) using MTS assay was investigated (Fig. 1a). AZD3759 alone significantly inhibited the proliferation of H3255 and PC-9 cells, with GI50 7.6 nM and 8.9 nM, respectively. Whereas, EGFR WT cells were insensitive to AZD3759, with GI50 > 5 μM in H226 cells and hardly any effect in H2228 cells. When AZD3759 was combined with radiation, a synergistic effect on inhibiting of cell proliferation was detected in H3255 cells treated with 10 nM AZD3759 and in PC-9 cells treated with 30 nM AZD3759 (CI < 1, Supporting Information Table S1 and Fig. S1), whereas an antagonistic effect was detected when AZD3759 at the low concentration (<10 nM in H3255 cells and <30 nM in PC-9 cells). In H226 and H2228 cells, there was antagonistic effect even the concentration of AZD3759 was up to 30 μM (CI > 1, data not shown). The survival of cells treated with either radiation or AZD3759 in combination with radiation by using CFA (Fig. 1b and Supporting Information Table S2) was evaluated next. In PC-9 cells, a synergistic effect on inhibiting cell survival was detected when 10 nM AZD3759 was combined with radiation, with DEF of 1.82 (p < 0.0001, AZD3759 10 nM with radiation vs. radiation alone). In contrast, there was no synergistic effect when AZD3759 at the concentration of 5 nM (p = 0.383, AZD3759 5 nM with radiation vs. radiation alone), even a radiosensitizing effect was detected (DEF = 1.1). Similarly, there was no synergistic effect by AZD3759 and radiation in H226 cells either, even the concentration of AZD3759 was increased to higher than 100 nM. These results demonstrate that both the sensitivity to AZD3759 and the concentration of AZD3759 are essential for synergistic effect between AZD3759 and radiation. Reference: Int J Cancer. 2018 Jul 1;143(1):212-224. https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31303|
|In vivo activity:||Following oral dosing in rats at 2 mg/kg, absorption of Zorifertinib (AZD3759) is rapid with blood Cmax of 0.58 μM achieved at 1.0 h. Subsequently, blood concentrations of Zorifertinib decline monoexponentially with a mean elimination half-life of 4.3 h, which is close to the same parameter obtained from intravenous dosing of 4.1 h. The bioavailability following an oral dose in rats is 91%. Blood pharmacokinetic parameters of Zorifertinib in male dogs are determined following both a single dose intravenous infusion and oral administration. Following the IV dose in dogs, Zorifertinib blood clearance is determined as 14 mL/min per kg, and the volume of distribution is 6.4 L/kg. Its elimination half-life is 6.2 h. Absorption of Zorifertinib is rapid with blood Cmax (698 nM) occurring between 0.5 and 1.5 h. The oral bioavailability of Zorifertinib is excellent at 90%. Zorifertinib demonstrated significant dose-dependent antitumor efficacy (78% tumor growth inhibition at 7.5 mg/kg qd and tumor regression at 15 mg/kg qd, respectively, 4 weeks after treatment) with <20% body weight loss, whereas CP-358774 has a limited effect in this model. At the end of the study, brain tissues are collected for histological assessment. Significantly decreased tumor area is observed by Zorifertinib treatment at the doses of 7.5 and 15 mg/kg. In addition, modulation of pEGFR is detected by a single dose of Zorifertinib at 15 mg/kg 1h after dosing, which confirmed target engagement by Zorifertinib. Reference: J Med Chem. 2015 Oct 22;58(20):8200-15. https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01073|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
|Soluble in DMSO, not in water||92.0||200.04|
The following data is based on the product molecular weight 459.91 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Chao D, Pang L, Shi Y, Wang W, Liu K. AZD3759 induces apoptosis in hepatoma cells by activating a p53-SMAD4 positive feedback loop. Biochem Biophys Res Commun. 2019 Feb 5;509(2):535-540. doi: 10.1016/j.bbrc.2018.12.102. Epub 2018 Dec 28. PMID: 30598263. 2. Zeng Q, Wang J, Cheng Z, Chen K, Johnström P, Varnäs K, Li DY, Yang ZF, Zhang X. 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. doi: 10.1021/acs.jmedchem.5b01073. Epub 2015 Oct 9. PMID: 26313252. 3. Xiong S, Xue M, Mu Y, Deng Z, Sun P, Zhou R. Determination of AZD3759 in rat plasma and br|
|In vitro protocol:||1. Chao D, Pang L, Shi Y, Wang W, Liu K. AZD3759 induces apoptosis in hepatoma cells by activating a p53-SMAD4 positive feedback loop. Biochem Biophys Res Commun. 2019 Feb 5;509(2):535-540. doi: 10.1016/j.bbrc.2018.12.102. Epub 2018 Dec 28. PMID: 30598263.|
|In vivo protocol:||1. Zeng Q, Wang J, Cheng Z, Chen K, Johnström P, Varnäs K, Li DY, Yang ZF, Zhang X. 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. doi: 10.1021/acs.jmedchem.5b01073. Epub 2015 Oct 9. PMID: 26313252. 2. Xiong S, Xue M, Mu Y, Deng Z, Sun P, Zhou R. Determination of AZD3759 in rat plasma and brain tissue by LC-MS/MS and its application in pharmacokinetic and brain distribution studies. J Pharm Biomed Anal. 2017 Jun 5;140:362-366. doi: 10.1016/j.jpba.2017.03.056. Epub 2017 Mar 31. PMID: 28399431.|
1: Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016 Mar;93:59-68. doi:
10.1016/j.lungcan.2016.01.003. Epub 2016 Jan 8. Review. PubMed PMID: 26898616.
2: Zeng Q, Wang J, Cheng Z, Chen K, Johnström P, Varnäs K, Li DY, Yang ZF, Zhang X. 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. doi: 10.1021/acs.jmedchem.5b01073. Epub 2015 Oct 9. PubMed PMID: 26313252.