AZD-9291

AZD-9291, also known as Osimertinib and Mereletinib, is a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors. AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines. AZD-9291 was approved in Nov. 2015 by FDA.

Product information

CAS Number: 1421373-65-0

Molecular Weight: 499.61

Formula: C28H33N7O2

Synonym:

Mereletinib

Osimertinib free base

Tagrisso

AZD 9291

AZD9291

AZD-9291

AZD-9291 freebase

trade name Tagrisso

Chemical Name:    N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

Smiles: CN(C)CCN(C)C1=CC(OC)=C(C=C1NC(=O)C=C)NC1=NC(=CC=N1)C1=CN(C)C2=CC=CC=C12

InChiKey: 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)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

AZD-9291 shows similar potency to early generation tyrosine kinase inhibitor (TKIs) in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for AZD-9291. AZD-9291 also potently inhibits phosphorylation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM.

In Vivo:

The tumor-bearing mice are treated with AZD-9291 (5 mg/kg/day) for one to two weeks. Within days of treatment, 5 of 5 C/L858R mice displays nearly 80% reduction in tumor volume by magnetic resonance imaging MRI after therapy with AZD-9291, while 5 of 5 mice treated with vehicle shows tumor growth. AZD-9291 demonstrates improved rat PK, reduced hERG affinity, and improved IGF1R margins relative to the previously described compounds, and so this compound is selected for further investigation. AZD-9291 also offers an additional degree of broader chemical and profile diversity when compared to the previously described lead compounds. Upon dosing AZD-9291 in three efficacy models, The comparable efficacy is observed at relatively low doses (10 mg/kg per day). The excellent efficacy is also observed when AZD-9291 is dosed at 5 mg/kg per day.

References:

1. Zhang Z, Yang S, Wang Q. Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-mutant lung cancer. Biomark Res. 2019 Nov 21;7:27. doi: 10.1186/s40364-019-0179-6. eCollection 2019. Review. PubMed PMID: 31832192; PubMed Central PMCID: PMC6873421.
2. Shetty V, Babu S. Management of CNS metastases in patients with EGFR mutation-positive NSCLC. Indian J Cancer. 2019 Nov;56(Supplement):S31-S37. doi: 10.4103/ijc.IJC_455_19. Review. PubMed PMID: 31793440.
3. Doval DC, Desai CJ, Sahoo TP. Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors. Indian J Cancer. 2019 Nov;56(Supplement):S23-S30. doi: 10.4103/ijc.IJC_449_19. Review. PubMed PMID: 31793439.
4. Zhu VW, Klempner SJ, Ou SI. Receptor Tyrosine Kinase Fusions as an Actionable Resistance Mechanism to EGFR TKIs in EGFR-Mutant Non-Small-Cell Lung Cancer. Trends Cancer. 2019 Nov;5(11):677-692. doi: 10.1016/j.trecan.2019.09.008. Epub 2019 Oct 29. Review. PubMed PMID: 31735287.

Products are for research use only. Not for human use.