Afatinib and Impurities
179552-74-0
Afatinib Impurity 5
179552-74-0
1456696-14-2 (keto form)
1456696-14-2 (keto form)
850140-73-7
Afatinib Impurity F
850140-73-7
1680184-59-1
1680184-59-1
945553-91-3
Afatinib Impurity C
945553-91-3
1449430-45-8
Afatinib Impurity 2
1449430-45-8
314771-76-1
Afatinib Impurity B
314771-76-1
402855-07-6
Afatinib Impurity A
402855-07-6
850140-72-6
Afatinib
850140-72-6

Background


Afatinib’s chemical name is (S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6 -yl)-4-(dimethylamino)but-2-enamide. It is a potent, irreversible dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Afatinib is the first irreversible ErbB family blocker. On July 12, 2013, the US Food and Drug Administration (FDA) announced that Afatinib has been approved for the treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) patients.

Indication

Afatinib is a kinase inhibitor indicated as monotherapy 3 for the first-line Label treatment of (a) Epidermal Growth Factor Receptor (EGFR) TKI (tyrosine kinase inhibitor)-naive adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have non-resistant EGFR mutations as detected by an FDA-approved test Label, and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy Label,3.

Recently, as of January 2018, the US FDA approved a supplemental New Drug Application for Boehringer Ingelheim's Gilotrif (afatinib) for the first line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test 4. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I 4.

Associated Conditions

Metastatic Non-Small Cell Lung Cancer

Refractory, metastatic squamous cell Non-small cell lung cancer

TARGET: Epidermal growth factor receptor, Receptor tyrosine-protein kinase erbB-2, Receptor tyrosine-protein kinase erbB-4

ACTIONS: inhibitor

Synthesis

Afatinib

References:
1. WO0250043A1.
2. J. Med. Chem. 2009, 52, 6880–6888.
3. CN103755688A.
4. CN103965120A.


Afatinib

References:
1. US20050085495A1.
2. Bioorg. Med. Chem. 2013, 21, 7988-7998.
3. J. Org. Chem. 1986, 51, 616-620.
4. WO2007085638A1.


Afatinib

References:
1. CN103242303A.
2. WO2014183560A1.
3. CN103288808A.


Afatinib

References:
1. CN103254156A.
2. CN103254182A.
3. CN103254183A.
4. WO2014180271A1.

Clinical Trial Information

NCT Number Phase Status Date Conditions Sponsor/Collaborators
NCT02423525   Recruiting 2019-05-16 Brain Cancer Santosh Kesari
NCT02372006   Recruiting 2019-05-13 Neuroectodermal TumorsRhabdomyosarcoma Boehringer Ingelheim
NCT02780687   Active, not recruiting 2019-05-13 Urologic Neoplasms Boehringer Ingelheim
NCT03157089   Active, not recruiting 2019-05-13 Carcinoma, Non-Small-Cell Lung Boehringer Ingelheim

Literatures

Publication Date Title Journal
2017-01-01 YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PloS one
2016-07-28 Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers. Journal of medicinal chemistry
2016-03-15 EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer research
2015-09-01 Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. The Lancet. Oncology
2013-10-01 Targeted therapies: Afatinib--new therapy option for EGFR-mutant lung cancer. Nature reviews. Clinical oncology