AZD-9291 is an irreversible inhibitor of mutant EGFR kinase 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].
AZD-9291是一种不可逆的突变型EGFR激酶选择性抑制剂，对L858R/T790M、ex19del和野生型EGFR的IC50值分别为15nM、17nM和480nM [1]。
一系列的突变导致EGFR耐药，AZD-9291是为突变EGFR开发的一种不可逆选择性抑制剂。AZD-9291通过靶向Cys 797来结合EGFR的ATP结合位点。在EGFR重组酶测定中，AZD-9291对突变型EGFR的亲和力比野生型EGFR高出约200倍。AZD-9291对其他受体酶的活性影响不显著。体外实验表明，AZD-9291可以抑制细胞系中的EGFR磷酸化，突变型EGFR的抑制效果比野生型细胞系更强。此外，AZD-9291可以在低剂量下诱导突变型EGFR在异种移植瘤模型中显著萎缩。这也出现在转基因小鼠肿瘤模型中。接受5mg/kg/天AZD9291治疗的小鼠肿瘤体积减少了80% [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.