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发表于 2013-5-14 09:59:44
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来自： 美国
jaydad 发表于 2013-5-12 03:23 
1- 手术后的分期是什么？分化程度如何？
IIB, T1N1M0. 中高 moderate to well differentiated adenocar ...
问得好. 我答的只代表个人意见和偏见.
两个都是 2,4-氨基嘧啶 结构(2,4-aminopyrimidine derivatives). The biggest difference between LDK378 (C28H36ClN5O3S) and AP26113 (C26H34ClN6O2P) is toxicity profile. LDK 侧链是硫(sulfonyl 磺酰), AP侧链是磷(phosphoryl 磷酰).
以下是我几天前在肺癌谣言榜INSPIRE.COM上发的评论
2nd gen ALKi: LDK378 vs AP26113
From an insider and key figure in the development of ALKi agents, I learned recently that
1) LDK378 was meant to compete with Pifizer's Xalkori/ crizotinib. It is by Pharma giant Novartis 诺华制药, and it surely will win the race to reach the market over Ariad. It may even take significant chunk of market from Xalkori/ crizotinib;
2) Exactly because of the rush to ca$h, Novartis R&D did not do a good job in fine tuning the selection of candidate for final development.
Based on my own information not from the "insider" above, LDK378 is basically a trim-down version of the former ALKi agent TAE684, which was published here - http://www.pnas.org/content/104/1/270.full
Though Novartis is very shy about showing it, I have the exact formular structure for LDK378 in case anyone wants it.
I think the problem with TAE684/ LDK378 lies in its sulfonyl side chain structure. It is almost apparent now that Norvatis wasn't able to bring TAE684 to the clinic/market likely due to toxicity concerns and subsequently lost the honor of "ALKi First-to-Market" to Pfizer's crizotinib. Whereas Novartis really should have reinvented and replaced the sulfonyl phenyl (磺酰苯基) side chain with something else, what they did was - they picked up a trim-down version of TAE684 likely with slightly lower toxicity but still with intact sulfonyl phenyl side chain. Let me ask you, what natural molecules in our body that has a sulfonyl group? None! It has to be detoxified before it can be eliminated and excreted out. What organ does detoxification?
3) On the opposite, the scientist(s) took their time at Ariad. They are a small company, can't afford to risk mistake. Ap26113 is going to be either their 2nd (blockbuster) success or 1st (major/catastrophic) failure. Their development of the leukemia drug ponatinib (Iclusig) really reflect the respect for science and pursuit of the best molecule. I don't have more info about AP26113 than all that is in the public domain, but I can tell you for sure that everything else being about equal, in place of LDK378's sulfonyl phenyl group, AP26113 has the phosphonyl phenyl (磷酰苯基)group. Hey, everyone, are we going to worry about a little extra phosphate-containing molecules in our body? I think not.
Disclaimer: I am on AP26113 and do own a few hundred shares of Ariad stock. So, your loss may even become my gain, as much as a few hundred $.
补充: 谁在幕后为争$把WZ4002发现发明人告上法庭, 害得美国EGFR阳性肺癌病人失去一二代药失效后的生存机会?
NOVARTIS - "诺华制药抢钱公司" |
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发表于 2013-5-11 19:03:16
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