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Description of AZD-9291: AZD-9291 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
Current developer: AstraZenca
Note: The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.
Protocols from literature
AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; <25nM) and EGFRm+/T790M (e.g. H1975; <25nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; >500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/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 5mg/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. Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma. (http://mct.aacrjournals.org/content/12/11_Supplement/A109.short)
1: Targeting resistance in lung cancer. Cancer Discov. 2013 Dec;3(12):OF9. doi: 10.1158/2159-8290.CD-ND2013-025. Epub 2013 Nov 7. PubMed PMID: 24327718.
2. Butterworth, Sam; Finlay, Maurice Raymond Verschoyle; Ward, Richard Andrew; Kadambar, Vasantha Krishna; Chandrashekar, Reddy C.; Murugan, Andiappan; Redfearn, Heather Marie. Preparation of 2-(2,4,5-substituted-anilino)pyrimidine derivatives as EGFR modulators useful for treating cancer. PCT Int. Appl. (2013), WO 2013014448 A1 20130131.
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