非常期待！
希望早日出来啊
愿新药早日研发出来，惠及广大病患
EAI045的原版英文文章谁能找到么？目前看到的，都是国内翻译的，想看一下英文原版出处
总是好消息，希望能早日应用
本帖最后由 Allenturf 于 2016-8-19 00:47 编辑
hsriver 发表于 2016-8-18 01:40
EAI045的原版英文文章谁能找到么？目前看到的，都是国内翻译的，想看一下英文原版出处
Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors
Yong Jia, Cai-Hong Yun, Eunyoung Park, Dalia Ercan, Mari Manuia, Jose Juarez, Chunxiao Xu, Kevin Rhee, Ting Chen, Haikuo Zhang, Sangeetha Palakurthi, Jaebong Jang, Gerald Lelais, Michael DiDonato, Badry Bursulaya, Pierre-Yves Michellys, Robert Epple, Thomas H. Marsilje, Matthew McNeill, Wenshuo Lu, Jennifer Harris, Steven Bender, Kwok-Kin Wong, Pasi A. Jänne & Michael J. Eck
AffiliationsContributionsCorresponding author
Nature 534, 129–132 (02 June 2016) doi:10.1038/nature17960
Received 15 October 2015 Accepted 29 March 2016 Published online 25 May 2016
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The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase1, 2, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor3, 4. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant5, 6, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond7. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization9, 10, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.
http://www.nature.com/nature/journal/v534/n7605/full/nature17960.html
希望早日造福患者们，关键是价格用得起吗？纯进口的也就有钱人用用。
漓江渔翁 发表于 2016-5-30 15:29
三代TKI耐药时：
1.如果新突变只有C797S,能用回一代TKI；
2.如果三代TKI耐药出现C797S和T ...
这个问题提的好
大家好！谁能告诉我184耐药后如何是好！换哪种药呢？谢谢！
有希望有未来!