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1 + 1 > 2的“合體”抗癌神藥——《Nature》報道新一代靶向mTOR抑制劑

  • 癌癥,神藥,抗癌

眾所周知,癌癥非常難纏?!都~約時報》最近刊登了一篇文章,充分說明了癌癥是多么狡猾。一位身患甲狀腺癌的婦女對常用化療藥依維莫司和西羅莫司產生了抗藥 性,這兩種藥都是通過抑制一種叫做mTOR的酶來殺死癌細胞的,而mTOR能夠促進細胞尤其是癌細胞的生長。但她的癌細胞已經變異,這些藥物對她無效了。


來自加州大學舊金山分校Kevan Shokat紀念斯隆-凱特琳癌癥中心Neal Rosen以及合作者報道了一種新型mTOR抑制劑,它比已有的抑制劑更加強大,如依維莫司,而且產生耐藥性的可能性更小。他們非常巧妙的將兩種作用于不同靶點的mTOR抑制劑雷帕霉素(rapamycin)MLN0128組合在一起,合成了新的二聯體分子RapaLink-1,它可以同時靶向mTOR酶上的兩個靶點。(Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature, DOI: 10.1038/nature17963)


圖1. RapaLink-1中,一個聚乙二醇連接分子(黑色)將雷帕霉素(藍色)和MLN0128(紅色)連接起來。圖片來源:NPG


Shokat已經通過Kura Oncology公司將該新藥的設計申請了專利。而來自麥吉爾大學的癌癥和mTOR專家Nahum Sonenberg評價此項工作對癌癥治療有重大影響。

圖2. 上圖蛋白印跡實驗表明RapaLink-1的作用靶點確實與雷帕霉素和MLN0128相同;下圖表明RapaLink-1對癌細胞的殺滅能力高于單獨使用雷帕霉素和MLN0128,甚至比雷帕霉素+ MLN0128的組合用藥效果更好。圖片來源:NPG


mTOR 控制著一條大部分人類癌癥中都很活躍的細胞信號通路,科學家們已經發展了依維莫司和西羅莫司等藥物來抑制這條通路。這些藥物都是細菌天然產物雷帕霉素的類 似物,靶向mTOR上的雷帕霉素結合位點。最近發展的第二代mTOR抑制劑則是通過靶向另一個mTOR位點工作。該位點通常與三磷酸腺苷(ATP)結合。 一些第二代抑制劑已經進入到臨床試驗階段。


不幸的是,癌細胞有強大的變異能力產生抗藥性,可以使第一代和第二代mTOR抑制劑失效。


研究者發現mTOR上的兩個結合位點相距不過15?。因此他們用一個長度合適的聚乙二醇連接分子將第一代抑制劑雷帕霉素和第二代抑制劑MLN0128連接到一起。新分子能夠跨越兩個結合位點,同時與它們結合。這就是第三代mTOR抑制劑,RapaLink-1。

圖3. RapaLink-1的合成路線,其中用了一步click反應。圖片來源:NPG


圖4. mTOR的結構示意圖,長長的連接分子(圖中虛線)使RapaLink-1可以同時結合到兩個靶點上。圖片來源:NPG


在細胞實驗和小鼠實驗中,RapaLink-1展現了強大的抗癌活性,而且沒有發現抗藥性。

圖5. 由于RapaLink-1需要剛好與相距不遠的兩個位點結合,連接分子的長度非常有講究。文章準備了三種不同長度的連接分子(如右圖),分別測試了它們與 mTOR的結合能力,不管是實驗(左上)還是計算化學(左下)結果都表明RapaLink-1和RapaLink-2的長度最合適,RapaLink-3 太短。圖片來源:NPG


德納-法伯癌癥研究所的激酶抑制劑專家Nathanael Gray表示他原本不看好這么大的分子會有好的療效。但是RapaLink-1有兩個特點,第一,它是兩種抑制劑的二聯體;第二,它能在紅細胞上富集,被運送至腫瘤部位。這或許能夠解釋它為什么效果這么好。癌細胞想再通過變異來對抗RapaLink-1恐怕不會那么容易了,因為它需要同時變異兩次。


圖6. RR1變異產生對雷帕霉素的抗藥性,TKi-R變異產生對AZD8055/ MLN0128的抗藥性,圖中可見當發生這兩種變異后,雷帕霉素或AZD8055便不能有效控制腫瘤的體積,而RapaLink-1對這兩種抗性變異都有效果。圖片來源:NPG


對于癌癥、病毒、細菌等狡猾多端的敵人,抗藥性一直令人頭疼的問題,雞尾酒療法是比較成功的延遲抗藥性的方法。但雞尾酒療法多是簡單的藥物組合,需要病人同 時服用多種藥物,副作用較強,病人的依從性不佳。而本文將多個活性分子連接成一個分子,通過精妙的結構控制使其發揮1+1 > 2的效果,為新型抗癌、抗病毒、抗菌藥物的設計提供了新思路和范本,希望RapaLink-1能早日用于臨床。

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