AZD-9291
AZD-9291 is an irreversible inhibitor of mutant EGFR with IC50 values of 15nM, 17nM and 480nM, respectively for L858R/T790M, ex19del and wild-type EGFR [1].
A series of mutations cause the resistance of EGFR, AZD-9291 is developed for an irreversible and selective inhibitor of the mutant EGFR. AZD-9291 binds to the ATP binding site of EGFR by targeting Cys 797. In EGFR recombinant enzyme assay, AZD-9291 shows about 200 times greater potency against the mutant EGFR than wild-type EGFR. AZD-9291 does not exhibit significant activity towards other receptor kinase. In vitro assays show that AZD-9291can inhibit EGFR phosphorylation with lower IC50 value in cell lines harboring sensitising EGFR mutants than in wild-type cell lines. Additionally, AZD9291 can induce profound shrinkage in mutant EGFR at low doses in xenograft models. This also happens in transgenic mouse tumor models. Mice treated with AZD9291 at the dose of 5 mg/kg/day display 80% reduction in tumor volume [1].
References:
[1] Darren A. E. Cross, Susan E Ashton, Serban Ghiorghiu, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discovery. 2014, June.
- 1. Hu X, Zhang ZY, et al. "A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress." Phytomedicine. 2020;68:153189. PMID:32070867
- 2. Richtmann S, Wilkens D, et al. "FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC." Cancers (Basel). 2019 May 11;11(5). pii: E652. PMID:31083571
- 3. Cheriyan VT, Alsaab H, et al. "A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers." Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID:30038713
| Storage | Store at -20°C |
| M.Wt | 499.61 |
| Cas No. | 1421373-65-0 |
| Formula | C28H33N7O2 |
| Synonyms | osimertinib |
| Solubility | ≥24.98 mg/mL in DMSO; insoluble in H2O; ≥8.09 mg/mL in EtOH with ultrasonic |
| SDF | Download SDF |
| Canonical SMILES | CN1C=C(C2=NC(NC3=C(OC)C=C(N(CCN(C)C)C)C(NC(C=C)=O)=C3)=NC=C2)C4=C1C=CC=C4 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment[1]: | |
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Cell lines |
Human lung cancer cells with EGFR-mutations or wild type EGFR stable expression |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Applications |
AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; < 25 nM) and EGFR m+/T790M (e.g. H1975; < 25 nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; > 500 nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. |
| Animal experiment[1]: | |
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Animal models |
EGFRm+ and EGFRm+/T790M transgenic mice |
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Dosage form |
5 mg/kg |
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Applications |
AZD9291 administered once daily orally at 5 mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5 mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: 1. Darren Cross1, Sue Ashton1, Caroline Nebhan2 et al. AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma. Mol Cancer Ther 2013;12(11 Suppl):A109. |
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| Description | AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of mutated forms EGFR with IC50 values of 12.92 nM, 11.44 nM and 493.8 nM for Exon 19 deletion EGFR, L858R/T790M EGFR and wild type EGFR, respectively. | |||||
| Targets | Exon 19 deletion EGFR | L858R/T790M EGFR | wild type EGFR | |||
| IC50 | 12.92 nM | 11.44 nM | 493.8 nM | |||
Quality Control & MSDS
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