afatinib   Click here for help

GtoPdb Ligand ID: 5667

Synonyms: BIBW2992 | Gilotrif®
Approved drug PDB Ligand
afatinib is an approved drug (EMA & FDA (2013))
Compound class: Synthetic organic
Comment: Afatinib is a second-generation, irreversible, covalently-bound EGFR tyrosine kinase inhibitor. It potently and selectively inhibits EGFR and Erbb2 [3,5,7]. Although afatinib demonstrates improved activity against the gatekeeper EGFR T790M resistance mutation, it is equally potent against the wild-type receptor, leading to dose-limiting toxicities and a narrow safety window [8]. Third generation, wild-type sparing inhibitors such as nazartinib are in development to circumvent this problem [4].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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View more information in the IUPHAR Pharmacology Education Project: afatinib

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 88.61
Molecular weight 485.16
XLogP 3.1
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CN(CC=CC(=O)Nc1cc2c(ncnc2cc1OC1COCC1)Nc1ccc(c(c1)Cl)F)C
Isomeric SMILES CN(C/C=C/C(=O)Nc1cc2c(ncnc2cc1O[C@@H]1COCC1)Nc1ccc(c(c1)Cl)F)C
InChI InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1
InChI Key ULXXDDBFHOBEHA-CWDCEQMOSA-N
References
1. Coumar MS, Chu CY, Lin CW, Shiao HY, Ho YL, Reddy R, Lin WH, Chen CH, Peng YH, Leou JS et al.. (2010)
Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.
J Med Chem, 53 (13): 4980-8. [PMID:20550212]
2. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011)
Comprehensive analysis of kinase inhibitor selectivity.
Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]
3. Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J et al.. (2008)
A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours.
Br J Cancer, 98 (1): 80-5. [PMID:18026190]
4. Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL et al.. (2016)
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 Res, 76 (6): 1591-602. [PMID:26825170]
5. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F et al.. (2008)
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
Oncogene, 27 (34): 4702-11. [PMID:18408761]
6. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010)
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
Chem Biol, 17 (11): 1241-9. [PMID:21095574]
7. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M et al.. (2010)
Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors.
J Clin Oncol, 28 (25): 3965-72. [PMID:20679611]
8. Yu HA, Pao W. (2013)
Targeted therapies: Afatinib--new therapy option for EGFR-mutant lung cancer.
Nat Rev Clin Oncol, 10 (10): 551-2. [PMID:23959269]