Osimertinib
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Identification
- Summary
Osimertinib is a tyrosine kinase inhibitor used in the treatment of certain types of non-small cell lung carcinoma.
- Brand Names
- Tagrisso
- Generic Name
- Osimertinib
- DrugBank Accession Number
- DB09330
- Background
Osimertinib is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals.1,9 Its use is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in cases where tumour EGFR expression is positive for the T790M mutation as detected by FDA-approved testing and which has progressed following therapy with a first-generation EGFR tyrosine kinase inhibitor. Approximately 10% of patients with NSCLC have a rapid and clinically effective response to EGFR-TKIs due to the presence of specific activating EGFR mutations within the tumour cells.2 More specifically, deletions around the LREA motif in exon 19 and exon 21 L858R point mutations are correlated with response to therapy.3
Development of third-generation EGFR-TKIs, such as osimertinib, has been in response to altered tumour resistance patterns following treatment and toxic side effects that impact patient quality of life. Treatment with first-generation EGFR-TKIs (gefitinib and erlotinib) has been associated with the development of resistance through activating mutations in the EGFR gene. Second-generation EGFR-TKIs (afatinib and dacomitinib) were then developed to be more potent inhibitors, although their use is associated with increased toxicity through nonspecific targeting of wild-type EGFR. In contrast, third-generation inhibitors are specific for the gate-keeper T790M mutations which increases ATP binding activity to EGFR and result in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.1,2,6
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 499.619
Monoisotopic: 499.269573331 - Chemical Formula
- C28H33N7O2
- Synonyms
- Mereletinib
- N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
- Osimertinib
- Osimertinibum
- External IDs
- AZD 9291
- AZD-9291
- AZD9291
Pharmacology
- Indication
Osimertinib is indicated for the:
- adjuvant treatment of non-small cell lung cancer (NSCLC) after tumour resection in adult patients whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.10
- first-line treatment of adult patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.10
- in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.10
- treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.10
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used as adjunct in combination to treat Locally advanced non-small cell lung cancer Regimen in combination with: Pemetrexed (DB00642) •••••••••••• ••••• •••••• Used as adjunct in combination to treat Locally advanced non-small cell lung cancer Regimen in combination with: Pemetrexed (DB00642) •••••••••••• ••••• •••••• Used as adjunct in combination to treat Metastatic non-small cell lung cancer Regimen in combination with: Pemetrexed (DB00642) •••••••••••• ••••• •••••• Used as adjunct in combination to treat Metastatic non-small cell lung cancer Regimen in combination with: Pemetrexed (DB00642) •••••••••••• ••••• •••••• Treatment of Metastatic non-small cell lung cancer •••••••••••• ••••• •••••• •••••••• •••••• •••••••••• •••••• - Associated Therapies
- Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg.9
- Mechanism of action
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs.9 As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.8,7 Compared to wild-type EGFR, osimertinib has 200 times higher affinity for EGFR molecules with the L858R/T790M mutation in vitro.4,5
Target Actions Organism AEpidermal growth factor receptor inhibitorregulatorHumans - Absorption
The median time to Cmax was found to be 6 hours.9
- Volume of distribution
The mean volume of distribution at steady state is 918 L.9
- Protein binding
Plasma protein binding of osimertinib is 95%.9
- Metabolism
Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, that circulate at approximately 10% of the concentration of the parent compound. Biochemical assays have shown that AZ7550 has similar potency and efficacy to osimertinib, while AZ5104 is more potent against mutant and wild-type EGFR. The main metabolic pathways are oxidation (predominantly by CYP3A) and dealkylation.9
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- Route of elimination
Osimertinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.9
- Half-life
The population estimated mean half-life is 48 hours.9
- Clearance
Oral clearance is 14.3 L/hr.9
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of treated patients with 0.3% of these being fatal. There is also a change of QTc interval prolongation; electrocardiogram and electrolytes should be monitored in patients with a history or predisposition for QTc prolongation. Cardiomyopathy occurred in 3% of patients, therefore left ventricular ejection fraction (LVEF) should be measured at baseline and during treatment. Osimertinib can cause embryo-fetal toxicity, requiring female patients to take effective birth control during therapy and for 6 weeks after final dose.9
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Osimertinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Osimertinib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Osimertinib. Abrocitinib The serum concentration of Osimertinib can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Osimertinib can be decreased when combined with Acalabrutinib. - Food Interactions
- Avoid St. John's Wort. This herb induces the CYP3A metabolism of osimertinib, and therefore, dose adjustments are necessary if they must be co-administered.
- Take at the same time every day.
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Osimertinib mesylate RDL94R2A16 1421373-66-1 FUKSNUHSJBTCFJ-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tagrisso Tablet, film coated 80 mg Oral Astrazeneca Ab 2016-09-08 Not applicable EU Tagrisso Tablet, film coated 40 mg Oral Astrazeneca Ab 2016-09-08 Not applicable EU Tagrisso Tablet 80 mg Oral Astrazeneca Ab 2016-07-19 Not applicable Canada Tagrisso Tablet, film coated 40 mg Oral Astrazeneca Ab 2016-09-08 Not applicable EU Tagrisso Tablet, film coated 80 mg/1 Oral AstraZeneca Pharmaceuticals LP 2015-11-13 Not applicable US
Categories
- ATC Codes
- L01EB04 — Osimertinib
- Drug Categories
- Acids, Acyclic
- Acrylates
- Amides
- Amines
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (weak)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as n-alkylindoles. These are compounds containing an indole moiety that carries an alkyl chain at the 1-position.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Indoles and derivatives
- Sub Class
- N-alkylindoles
- Direct Parent
- N-alkylindoles
- Alternative Parents
- Aminophenyl ethers / Methoxyanilines / Indoles / Phenoxy compounds / Methoxybenzenes / Anisoles / Dialkylarylamines / Alkyl aryl ethers / Aminopyrimidines and derivatives / N-methylpyrroles show 8 more
- Substituents
- Alkyl aryl ether / Amine / Aminophenyl ether / Aminopyrimidine / Aniline or substituted anilines / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carboximidic acid show 27 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 3C06JJ0Z2O
- CAS number
- 1421373-65-0
- InChI Key
- DUYJMQONPNNFPI-UHFFFAOYSA-N
- InChI
- InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
- IUPAC Name
- N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
- SMILES
- COC1=C(NC2=NC=CC(=N2)C2=CN(C)C3=C2C=CC=C3)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C
References
- Synthesis Reference
Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL: Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1. Pubmed
- General References
- Xu M, Xie Y, Ni S, Liu H: The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). Ann Transl Med. 2015 May;3(7):96. doi: 10.3978/j.issn.2305-5839.2015.03.60. [Article]
- Tan CS, Gilligan D, Pacey S: Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015 Sep;16(9):e447-59. doi: 10.1016/S1470-2045(15)00246-6. [Article]
- Ayeni D, Politi K, Goldberg SB: Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer. Clin Cancer Res. 2015 Sep 1;21(17):3818-20. doi: 10.1158/1078-0432.CCR-15-1211. Epub 2015 Jul 13. [Article]
- Yosaatmadja Y, Silva S, Dickson JM, Patterson AV, Smaill JB, Flanagan JU, McKeage MJ, Squire CJ: Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-44. doi: 10.1016/j.jsb.2015.10.018. Epub 2015 Nov 2. [Article]
- Greig SL: Osimertinib: First Global Approval. Drugs. 2016 Feb;76(2):263-73. doi: 10.1007/s40265-015-0533-4. [Article]
- Shea M, Costa DB, Rangachari D: Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis. 2016 Apr;10(2):113-29. doi: 10.1177/1753465815617871. Epub 2015 Nov 30. [Article]
- Liao BC, Lin CC, Yang JC: Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015 Mar;27(2):94-101. doi: 10.1097/CCO.0000000000000164. [Article]
- Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61. doi: 10.1158/2159-8290.CD-14-0337. Epub 2014 Jun 3. [Article]
- FDA Approved Drug Products: TAGRISSO (osimertinib) tablets for oral use [Link]
- FDA Approved Drug Products: TAGRISSO (osimertinib) tablets, for oral use (February 2024) [Link]
- External Links
- Human Metabolome Database
- HMDB0248778
- PubChem Compound
- 71496458
- PubChem Substance
- 310265210
- ChemSpider
- 31042598
- BindingDB
- 50029668
- 1721560
- ChEBI
- 90943
- ChEMBL
- CHEMBL3353410
- ZINC
- ZINC000098023177
- PharmGKB
- PA166131626
- PDBe Ligand
- YY3
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Osimertinib
- PDB Entries
- 4zau / 6jwl / 6jx0 / 6jx4 / 6jxt / 6lud / 7jxm / 7jxp / 7jxw / 7k1h
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Non-Small Cell Lung Cancer (NSCLC) 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Non-Small Cell Lung Carcinoma 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Other Locally Advanced or Metastatic Non-small Cell Lung Cancer 1 somestatus stop reason just information to hide Not Available Completed Not Available Advanced Non-Small Cell Lung Cancer (NSCLC) / Third Generation TKI 1 somestatus stop reason just information to hide Not Available Completed Not Available EGFR Positive Non-small Cell Lung Cancer 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 40 mg Tablet Oral 80 mg Tablet Oral 80.000 mg Tablet, film coated Oral 40 mg/1 Tablet, film coated Oral 80 mg/1 Tablet, film coated Oral Tablet, film coated Oral 40 mg Tablet, film coated Oral 80 mg Tablet, coated Oral 40 mg Tablet, coated Oral 80 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8946235 No 2015-02-03 2032-08-08 US US9732058 No 2017-08-15 2032-07-25 US US10183020 No 2019-01-22 2035-01-02 US US11524951 No 2012-07-25 2032-07-25 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0224 mg/mL ALOGPS logP 4.47 ALOGPS logP 4.49 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 13.64 Chemaxon pKa (Strongest Basic) 8.87 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 87.55 Å2 Chemaxon Rotatable Bond Count 10 Chemaxon Refractivity 150.32 m3·mol-1 Chemaxon Polarizability 56.84 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0f6t-1000940000-881ac98115a67807e1c2 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-7009800000-261bd3bb771a787a5a9a Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0005-1000900000-0c69c2f1e82235236661 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00e9-7009210000-cf883a620bc54550c5d0 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-06r5-1001900000-6c90b48351349dcc0f86 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-01vk-1018900000-eb00242e73de11d1e619 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 222.40434 predictedDeepCCS 1.0 (2019) [M+H]+ 224.79991 predictedDeepCCS 1.0 (2019) [M+Na]+ 230.71243 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- InhibitorRegulator
- General Function
- Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity)
- Specific Function
- actin filament binding
- Gene Name
- EGFR
- Uniprot ID
- P00533
- Uniprot Name
- Epidermal growth factor receptor
- Molecular Weight
- 134276.185 Da
References
- Yosaatmadja Y, Silva S, Dickson JM, Patterson AV, Smaill JB, Flanagan JU, McKeage MJ, Squire CJ: Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-44. doi: 10.1016/j.jsb.2015.10.018. Epub 2015 Nov 2. [Article]
- Vasconcelos PENS, Gergis C, Viray H, Varkaris A, Fujii M, Rangachari D, VanderLaan PA, Kobayashi IS, Kobayashi SS, Costa DB: EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors. JTO Clin Res Rep. 2020 Sep;1(3). doi: 10.1016/j.jtocrr.2020.100051. Epub 2020 May 13. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Osimertinib FDA label [File]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
Drug created at November 18, 2015 17:23 / Updated at April 23, 2024 11:38