osimertinib   Click here for help

GtoPdb Ligand ID: 7719

Synonyms: AZD 9291 | AZD-9291 | AZD9291 | mereletinib (obsolete INN) | Tagrisso®
Approved drug PDB Ligand
osimertinib is an approved drug (FDA (2015), EMA (2016))
Compound class: Synthetic organic
Comment: Osimertinib (AZD9291) is a third-generation, potent, selective and irreversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase bearing mutations which either sensitise the receptor, or cause drug resistance (eg the T790M mutation) [2]. The compound is less effective against the wild-type receptor.
This compound is included in AstaZeneca's Open Innovation Pharmacology Toolbox. There are reports of acquired resistance to osimertinib with tumours developing the C797S [6,9] and L718Q mutations [1] .

Third-generation mutant EGFR inhibitors are being developed to circumvent dose-limiting WT EGFR-driven toxicities such as gastrointestinal toxicity and rash. The progress being made in developing advanced generation EGFR inhibitors is discussed by Yu and Riely (2013) [8] and Ou and Soo (2015) [4].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 11
Topological polar surface area 87.55
Molecular weight 499.27
XLogP 3.6
No. Lipinski's rules broken 0
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Canonical SMILES C=CC(=O)Nc1cc(Nc2nccc(n2)c2cn(c3c2cccc3)C)c(cc1N(CCN(C)C)C)OC
Isomeric SMILES C=CC(=O)Nc1cc(Nc2nccc(n2)c2cn(c3c2cccc3)C)c(cc1N(CCN(C)C)C)OC
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)
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Summary of Clinical Use Click here for help
A Phase 3 clinical trial (NCT02151981) is recruiting patients to compare AZD9291 vs. platinum-based doublet-chemotherapy in locally advanced or metastatic non-small cell lung cancer (Oct 2014). Click here to link to ClinicalTrials.gov's listing of AZD9291 trials. As a result of the FDA's accelerated approval program, osimertinib was approved in November 2015 for the treatment of patients with metastatic EGFRT790M mutation-positive NSCLC that has progressed on or after EGFR tyrosine kinase inhibitor therapy (and with the mutation confirmed using an FDA-approved test). This was converted to regular approval in March 2017. In April 2018 the FDA expanded osimertinib's approval to include use as a first-line treatment for metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations (again as detected by an FDA-approved test) [3].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04035486 A Study of Osimertinib With or Without Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (FLAURA2) Phase 3 Interventional AstraZeneca 5
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