General
Preferred name
AFATINIB
Synonyms
Afatinib Dimaleate, BIBW2992-MA2, BIBW-2992 ()
BIBW2992, Tovok ()
BIBW2992 ()
BIBW 2992MA2 ()
Afatinib (BIBW2992) Dimaleate ()
AFATINIB DIMALEATE ()
Afatinib (dimaleate) ()
BIBW2992 (Afatinib) ()
BIBW 2992 ()
Tovok ()
S1011 ()
(E/Z)-Afatinib ()
BIBW-2992 ()
GILOTRIF ()
GIOTRIF ()
NSC-750691 ()
Tomtovok ()
Afatinib (BIBW2992) ()
(E/Z)-BIBW 2992 ()
BIBW-2992MA2 ()
BIBW-2992 MA2 ()
BIBW-2992-MA2 ()
BIBW2992-MA2 ()
Afatinib maleate ()
BIBW2992 MA2 ()
Afatinib (maleate) ()
Afatinib-d6 ()
P&D ID
PD003373
CAS
439081-18-2
850140-72-6
850140-73-7
1254955-21-9
1313874-96-2
Tags
probe
covalent binder
drug
available
Approved by
EMA
FDA
First approval
2013
Drug Status
approved
Drug indication
Non-small-cell lung cancer
Max Phase
Phase 4
Probe info
Probe selectivity
protein-selective
Probe type
P&D approved
calculated probe
experimental probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
104
No orthogonal probes found
Similar probes
21
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
INDICATION
Afatinib is a kinase inhibitor indicated as monotherapy [L2937] for the first-line [FDA 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 [FDA Label], and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy [FDA Label, L2937].; ; 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 [L2939]. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I [L2939].
TOXICITY
Most common adverse reactions (≥20%) are diarrhea, rash/dermatitis, acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus [FDA Label].; ; Conversely, overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib (as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (< 1.5 times ULN) [L2937]. Both individuals recovered from these adverse events [L2937].
MOA
ATP-competitive inhibitor;covalent inhibitor
COMMENT
As a probe for ERBB2 this would not be recommended as it exhibits greater potency for EGFR, more suitable selective probes for ERBB2 exist. Treat the quoted biochemical potency with caution as it is an irreversible inhibitor. Hits WT and activating mutant forms of EGFR with similar potency. Jun 11 2016 - 4:18am; Potent irreversible inhibitor of EGFR and HER2. Some selectivity data are reported - ideally, a full kinase profile would be required to better understand higher dose range limit. Jun 11 2016 - 4:19am; Treat the quoted biochemical potency with caution as it is an irreversible inhibitor. Afatinib hits wild-type and activating-mutant forms of EGFR with similar potency. Aug 17 2016 - 6:28pm
DESCRIPTION
Afatinib is a second-generation, irreversible, covalently-bound EGFR tyrosine kinase inhibitor. It potently and selectively inhibits EGFR and Erbb2 . 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 . Third generation, wild-type sparing inhibitors such as are in development to circumvent this problem .
(GtoPdb)
ABSORPTION
Following oral administration, time to peak plasma concentration (Tmax) is 2 to 5 hours [FDA Label]. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg [FDA Label]. The geometric mean relative bioavailability of 20 mg tablets was 92% as compared to an oral solution [FDA Label].; ; Additionally, systemic exposure to afatinib is decreased by 50% (Cmax) and 39% (AUC0-∞), when administered with a high-fat meal compared to administration in the fasted state [L2937]. Based on population pharmacokinetic data derived from clinical trials in various tumor types, an average decrease of 26% in AUCss was observed when food was consumed within 3 hours before or 1 hour after taking afatinib [L2937].
PHARMACODYNAMICS
Aberrant ErbB signaling triggered by receptor mutations, and/or amplification, and/or receptor ligand overexpression contributes to the malignant phenotype [L2937]. Mutation in EGFR defines a distinct molecular subtype of lung cancer [L2937].; ; In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signaling resulting in tumor growth inhibition or tumor regression [L2937]. NSCLC tumors with common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical settings [L2937]. Limited non-clinical and/or clinical activity was observed in NSCLC tumors with insertion mutations in exon 20 [L2937].; ; The acquisition of a secondary T790M mutation is a major mechanism of acquired resistance to afatinib and gene dosage of the T790M-containing allele correlates with the degree of resistance in vitro [L2937]. The T790M mutation is found in approximately 50% of patients' tumors upon disease progression on afatinib, for which T790M targeted EGFR TKIs may be considered as a next line treatment option [L2937]. Other potential mechanisms of resistance to afatinib have been suggested preclinically and MET gene amplification has been observed clinically [L2937].; ; At the same time, the effect of multiple doses of afatinib (50 mg once daily) on cardiac electrophysiology and the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors [FDA Label]. Ultimately, no large changes in the mean QTc interval (i.e., >20 ms) were detected in the study [FDA Label].
MOA
Afatinib is a potent and selective, irreversible ErbB family blocker [L2937]. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 [L2937].; ; In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling [FDA Label]. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC [FDA Label]. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods [FDA Label]. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions [FDA Label].; ; Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients [FDA Label]. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2 [FDA Label].
MOA
ATP-competitive inhibitor, covalent inhibitor
(Chemical Probes.org)
DESCRIPTION
Afatinib is a kinase inhibitor indicated for the first-line treatment of patient with metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
(PKIDB)
DESCRIPTION
inhibitor of EGFR and HER2
(Informer Set)
DESCRIPTION
Potent and selective BTK inhibitor
(Tocris Bioactive Compound Library)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
582
Organisms
0
Compound Sets
41
Axon Medchem Screening Library
ChEMBL Approved Drugs
ChEMBL Drugs
Chemical Probes.org
Clinical kinase drugs
Concise Guide to Pharmacology 2017/18
Concise Guide to Pharmacology 2019/20
Concise Guide to Pharmacology 2021/22
Concise Guide to Pharmacology 2023/24
CovalentInDB
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
Enamine BioReference Compounds
EU-OPENSCREEN Bioactive Compound Library
EUbOPEN Chemogenomics Library
Guide to Pharmacology
High-quality chemical probes
Informer Set
Kinase Inhibitors (best-in-class)
LSP-MoA library (Laboratory of Systems Pharmacology)
LSP-OptimalKinase library (Laboratory of Systems Pharmacology)
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
Other bioactive compounds
PKIDB
ReFrame library
Selleckchem Bioactive Compound Library
Tocris Bioactive Compound Library
Tool Compound Set
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
62
Molecular Weight
485.16
Hydrogen Bond Acceptors
7
Hydrogen Bond Donors
2
Rotatable Bonds
8
Ring Count
4
Aromatic Ring Count
3
cLogP
4.39
TPSA
88.61
Fraction CSP3
0.29
Chiral centers
1.0
Largest ring
6.0
QED
0.46
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
EGFR
ERBB2
Receptor protein-tyrosine kinase erbB-2
ERBB2, EGFR
Epidermal growth factor receptor erbB1
EGFR (L858R)
EGFR (L858R/T790M)
EGFR (wt)
HER2
HER4
EGFR, ERBB2, ERBB4
EGFR/HER2 inhibitor
ErbB4
Akt
c-Met/HGFR
p38 MAPK
Autophagy,EGFR,HER2
EGFR, ERBB2
Compound status
clinical
Pathway
EGFR signaling
Angiogenesis
JAK/STAT Signaling
Tyrosine Kinase/Adaptors
Apoptosis
Autophagy
MAPK/ERK Pathway
PI3K/Akt/mTOR
Protein Tyrosine Kinase/RTK
Known off targets
ErbB2
Kinase group
TK
MOA
HER
Inhibitor
Irreversible EGFR (HER1
erbB1) Inhibitors
HER2 (erbB2) Inhibitors
Inhibitors of Signal Transduction Pathways
EGFR inhibitor
Member status
member
Indication
non-small cell lung cancer (NSCLC)
Orthogonal probe
Canertinib
Target subclass
RTK
RTK, RTK
Target class
Protein kinase
Kinase, Kinase
Source data
