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Zorifertinib
Zorifertinib
AZD 3759
CAS 1626387-80-1, 67SX9H68W2
WeightAverage: 459.91
Monoisotopic: 459.1473455
Chemical FormulaC22H23ClFN5O3
[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate
- [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate
- (4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl) (2R)-2,4-dimethylpiperazine-1-carboxylate
- (R)-4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl 2,4-dimethylpiperazine-1-carboxylate
- 4-[(3-CHLORO-2-FLUOROPHENYL)AMINO]-7-METHOXYQUINAZOLIN-6-YL (2R)-2,4-DIMETHYLPIPERAZINE-1-CARBOXYLATE
China 2024, APPROVALS 2024, Alpha Biopharma, ASTRA ZENECA, Zorifer,
Zorifertinib (AZD3759) is a drug for the treatment of cancer.[1] In China, it was approved in 2024 for locally advanced or metastatic non-small-cell lung cancer (NSCLC) that has epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutations and central nervous system (CNS) metastases.[2]
Zorifertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR), with potential antineoplastic activity. Upon oral administration, zorifertinib 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.
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J. Med. Chem. 58 (2015) 8200–8215.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01073
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European Journal of Medicinal Chemistry 291 (2025) 117643
Zorifertinib, developed by AstraZeneca as AZD3759, is a novel EGFR TKI designed to effectively penetrate the blood-brain barrier (BBB) [44,45]. In 2018, Alpha Biopharma, in collaboration with AstraZeneca, advanced its development. In 2024, the NMPA gave its approval to zorifertinib hydrochloride tablets, which are sold under the brand name Zorifer. This approval is for the use of these tablets in the first-line treatment of adult patients who have the following conditions: they
have locally advanced or metastatic NSCLC with either EGFR exon 19 deletion or exon 21 L858R substitution mutations, and also have CNSmetastases [45]. Zorifertinib exerts its pharmacological action through the selective inhibition of EGFR tyrosine kinase activity, with a particular focus on mutational forms such as L858R and exon 19 deletions. In contrast to several other tyrosine kinase inhibitors (TKIs), it does not serve as a substrate for BBB efflux transporters, namely P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This unique property enables zorifertinib to reach elevated concentrations within brain tissue and cerebrospinal fluid. As a result, it can effectively target and
act against CNS metastases [44,45]. The clinical efficacy of zorifertinib was demonstrated in the EVEREST study (NCT03653546), a random ized, open-label, international multicenter Phase II/III trial. The study
enrolled 492 patients with EGFR-mutant NSCLC and CNS metastases. Results showed that zorifertinib significantly improved systemic PFS to 9.6 months compared to 6.9 months with first-generation EGFR-TKIs, reducing the risk of disease progression or death by 28 %. Intracranial PFS was notably extended to 15.2 months versus 8.3 months in the control group. The ORR was 68.6 % for zorifertinib compared to 58.4 % for the control. Regarding toxicity, zorifertinib exhibited a manageable safety profile. The incidence of treatment-related adverse events (TRAEs) was similar between the zorifertinib and control groups (97.7 %vs. 94.0 %), with grade ≥3 TRAEs occurring in 65.9 % of patients receiving zorifertinib compared to 18.3 % in the control group. No new safety signals were identified, indicating an acceptable tolerability for patients. The approval of zorifertinib offers a significant advancement in
the treatment of EGFR-mutant NSCLC patients with CNS metastases,providing an effective therapeutic option capable of addressing both systemic and intracranial disease [44].
The synthesis of Zorifertinib, depicted in Scheme 11, initiates with nucleophilic substitution between Zori-001 and Zori-002 in MeCN, affording Zori-003 [46]. Hydrolysis of the ester moiety in Zori-003
yields Zori-004, which is subsequently esterified with Zori-005 in DMF to form Zori-006. Acidic deprotection of Zori-006 generates Zori-007, followed by methylation to deliver Zorifertinib. Concurrently, Zori-005 is prepared via amidation of Zori-008
[44] M. Roy-O’Reilly, D. Rogawski, The climb toward intracranial efficacy: Zorifertinib
in EGFR-mutant NSCLC with CNS metastases in the EVEREST trial, Med 6 (2025)
100525.
[45] Q. Zhou, Y. Yu, L. Xing, Y. Cheng, Y. Wang, Y. Pan, Y. Fan, J. Shi, G. Zhang, J. Cui,
J. Zhou, Y. Song, W. Zhuang, Z. Ma, Y. Hu, G. Li, X. Dong, J. Feng, S. Lu, J. Wu,
J. Li, L. Zhang, D. Wang, X. Xu, T.Y. Yang, N. Yang, Y. Guo, J. Zhao, Y. Yao,
D. Zhong, B. Xia, C.T. Yang, B. Zhu, P. Sun, B.Y. Shim, Y. Chen, Z. Wang, M.J. Ahn,
J. Wang, Y.L. Wu, First-line zorifertinib for EGFR-Mutant non-small cell lung
cancer with central nervous system metastases: the phase 3 EVEREST trial, Med 6
(2025) 100513.
[46] Q. Zeng, J. Wang, Z. Cheng, K. Chen, P. Johnstr¨om, K. Varn¨as, D.Y. Li, Z.F. Yang,
X. Zhang, 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. 58 (2015) 8200–8215.
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References
- Zhou Q, Yu Y, Xing L, Cheng Y, Wang Y, Pan Y, et al. (January 2025). “First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial”. Med. 6 (1) 100513. doi:10.1016/j.medj.2024.09.002. PMID 39389055.
- “Zorifertinib Receives NMPA Approval for EGFR+ NSCLC With CNS Metastases”. November 20, 2024.
| Clinical data | |
|---|---|
| Other names | AZD3759 |
| Legal status | |
| Legal status | Rx in China |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1626387-80-1 |
| PubChem CID | 78209992 |
| IUPHAR/BPS | 10456 |
| DrugBank | DB14795 |
| ChemSpider | 38772332 |
| UNII | 67SX9H68W2 |
| ChEMBL | ChEMBL3623290 |
| Chemical and physical data | |
| Formula | C22H23ClFN5O3 |
| Molar mass | 459.91 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////////Zorifertinib, china 2024, APPROVALS 2024, Alpha Biopharma, ASTRA ZENECA, Zorifer, AZD 3759, 67SX9H68W2
Camizestrant, AZD 9833
Camizestrant, AZD 9833
AZ 14066724
PHASE 2
CAS: 2222844-89-3
Chemical Formula: C24H28F4N6
Exact Mass: 476.2312
Molecular Weight: 476.5236
Elemental Analysis: C, 60.49; H, 5.92; F, 15.95; N, 17.64
N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine
- AZ14066724
- AZD-9833
- AZD9833
- Camizestrant
- UNII-JUP57A8EPZ
- WHO 11592
- OriginatorAstraZeneca
- ClassAmines; Antineoplastics; Azetidines; Fluorinated hydrocarbons; Isoquinolines; Pyrazolones; Pyridines; Small molecules
- Mechanism of ActionSelective estrogen receptor degraders
- Phase IIIBreast cancer
- 13 Jun 2022AstraZeneca initiates a phase I drug-drug interaction trial of AZD 9833 Healthy postmenopausal female volunteers, in USA (NCT05438303)
- 10 Jun 2022AstraZeneca and Quotient Sciences complete the phase I QSC205863 trial in Breast cancer (In volunteers) in United Kingdom (PO, Liquid) (NCT05364255)
- 03 Jun 2022Safety, efficacy and pharmacokinetics data from the phase I SERENA 1 trial for Breast cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
- Mechanism:selective estrogen receptor degrader
- Area under investigation:estrogen receptor +ve breast cancer
- Date commenced phase:Q1 2019
- Estimated Filing Acceptance:
- CountryDateUS: EU: Japan: China:
AZD9833 is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, SERD AZD9833 binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells
Camizestrant is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, camizestrant binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells
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https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0040-1719368
Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist J. Med. Chem. 2020, 63, 14530–14559, DOI: 10.1021/acs.jmedchem.0c01163.
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doi: 10.1021/acs.jmedchem.0c01163.
aReagents and Conditions: (a) n-BuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 1 h, 60%; (b) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 63-74% or isobutyrylaldehyde, Na(OAc)3BH, THF, 0 oC, 56%; (c) benzophenone imine, Pd2dba3, Rac-BINAP, NaOtBu, toluene, 90 oC, then 1 N aq. HCl, 71-85%; (d) nBuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 4 h; e) NH2OH, NH2OH.HCl, EtOH, reflux. 84% over 2 steps; (f) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 44-100% or 1-fluorocyclopropane-1- carboxylic acid, HATU, Et3N, DMF, RT, 61%, then BH3.THF, THF, 65 oC, 82%.
[α]26 D -147 (c 2.3, MeOH); 1H NMR (500 MHz, DMSO-d6, 27 °C) 1.08 (d, J = 6.6 Hz, 3H), 1.64 (dp, J = 25.0, 6.3 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.73(t, J = 6.8 Hz, 2H), 2.84 (dd, J = 17.1, 8.2 Hz, 1H), 2.96 (dt, J = 19.6, 9.8 Hz, 1H), 3.07 (dd, J = 17.2, 4.6 Hz, 1H), 3.49 (m, 1H), 3.50 – 3.58 (m, 1H), 3.58 – 3.66 (m, 2H), 3.92 (h, J = 6.5 Hz, 1H), 4.44 (dtd, J = 47.4, 6.1, 1.3 Hz, 2H), 4.93 (s, 1H), 6.23 (d, J = 6.9 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.83 (dt, J = 8.8, 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 1.3 Hz, 1H), 12.97 (s, 1H); 13C NMR (125 MHz, DMSO-d6, 27 °C) 16.2, 28.2 (d, J = 19.4 Hz), 30.1, 43.0, 47.3, 48.7 (q, J = 30.1 Hz), 54.8 (d, J = 5.6 Hz), 61.3 (2C), 67.1, 82.0 (d, J = 161.3 Hz), 107.5, 119.0, 122.4, 123.7, 126.1, 126.2 (q, J = 278.5 Hz), 126.4, 127.5, 131.7, 132.9, 138.5, 142.3, 150.0; 19F NMR (376 MHz, DMSO-d6, 27 °C) -218.1 (1F), -69.7 (3F); m/z (ES+), [M+H]+ = 477, HRMS (ESI) (MH+ ); calcd, 477.2408; found, 477.2390
/////////
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/////////////////////////////////////////////////////////////////////////////
AZD9833 is selective oestrogen receptor degrader (SERD). It works by breaking down the site where oestrogen attaches to the cancer cell. This can help stop or slow the growth of hormone receptor breast cancer. Researchers think that AZD9833 with palbociclib might work better than anastrozole and palbociclib.
AZD9833 + palbociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125 mg for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (1 mg, PO, once daily)
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (clinicaltrials.gov)…..https://veri.larvol.com/news/azd9833/drug
P1, N=305, Recruiting, AstraZeneca | Trial primary completion date: Dec 2022 –> Oct 2023
2 months ago
Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
| Description | Camizestrant (AZD-9833) is a potent and orally active estrogen receptor (ER) antagonist. Camizestrant is used for the study of ER+ HER2-advanced breast cancer[1]. |
|---|---|
| IC50 & Target | IC50: estrogen receptor (ER)[1] |
| In Vitro | Camizestrant is extracted from patent US20180111931A1, example 17[1].MCE has not independently confirmed the accuracy of these methods. They are for reference only. |
| In Vivo | Camizestrant (oral administration; 0.2-50 mg/kg; 20 days) exhibits anti-tumour efficacy as a dose-dependent manner in human parental MCF7 mice xenograft[1]. Camizestrant (oral administration; 0.8-40 mg/kg; 30 days) decreases tumor growth as a dose-dependent manner. It gives almost complete tumour growth inhibition at the doses >10 mg/kg in mice[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Model:Human ESR1 mutant breast cancer patient derived xenograft with CTC174 cells in female NSG mice[1]Dosage:0.8 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kgAdministration:Oral administration; 30 days; once dailyResult:Inhibited tumor growth in a dose-dependent manner. |
| Clinical Trial | NCT NumberSponsorConditionStart DatePhaseNCT04711252AstraZenecaER-Positive HER2-Negative Breast CancerJanuary 28, 2021Phase 3NCT04964934AstraZenecaER-Positive HER2-Negative Breast CancerJune 30, 2021Phase 3NCT04214288AstraZenecaAdvanced ER-Positive HER2-Negative Breast CancerApril 22, 2020Phase 2NCT04588298AstraZenecaHER2-negative Breast CancerNovember 2, 2020Phase 2NCT04541433AstraZenecaER&addition; HER2- Advanced Breast CancerSeptember 29, 2020Phase 1NCT03616587AstraZenecaER&addition; HER2- Advanced Breast CancerOctober 11, 2018Phase 1NCT04546347AstraZeneca|Quotient SciencesHealthy VolunteersSeptember 17, 2020Phase 1NCT04818632AstraZenecaER&addition;, HER2-, Metastatic Breast CancerOctober 11, 2021Phase 1 |
////////////Camizestrant, AZD 9833, AZ 14066724, UNII-JUP57A8EPZ, WHO 11592, PHASE 2, ASTRA ZENECA, CANCER
C[C@@H]1CC2=C3C(NN=C3)=CC=C2[C@@H](C4=NC=C(NC5CN(CCCF)C5)C=C4)N1CC(F)(F)F
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