Nat Commun:廈門大學張曉坤與蘇迎教授課題組發表抗腫瘤研究論文
2017年7月17日,國際學術權威刊物自然出版集團旗下子刊《Nature Communications》雜誌線上發表了廈門大學藥學院張曉坤教授與蘇迎教授課題組的最新研究成果。研究論文深入研究並揭示了小分子化合物K-80003發揮腫瘤特異性藥效的分子基礎,
廈大藥學院博士生陳鯉群和美國Sanford Burnham Prebys研究所的Alexander E. Aleshin為論文的共同第一作者,張曉坤教授和蘇迎教授為共同通訊作者。
腫瘤細胞的快速增殖一直是抗癌治療的難題所在,而一些抗癌藥物同時作用于癌細胞和健康細胞,造成“殺敵一萬,自損三千”的治療結果,也令患者痛苦和無奈。K-80003作為靶向抗癌藥物,自研發伊始,就表現出高效低毒的寶貴特性,其根本機理吸引著研究人員的關注。
追根溯源,還要從K-80003的作用靶點tRXRα說起。tRXRα是存在於腫瘤細胞和組織中的大量短蛋白片段,與腫瘤的發展密切相關。
K-80003的藥物研發緊鑼密鼓地開展,關於K-80003的具體入微的抗癌機制研究有待層層深入,
研究人員通過晶體結構分析等技術方法,結合裸鼠移植瘤實驗及MMTV-PyMT轉基因小鼠給藥實驗等一系列實驗的多角度論證,最終發現,K-80003是通過特異性地誘導短蛋白tRXRα形成四聚體,使得tRXRα喪失活性,從而中止了癌細胞的增殖。並且,K-80003不會對正常細胞中的全長蛋白RXRα產生作用,避免了誤傷健康細胞。
研究團隊中,張曉坤教授及其課題組是最早在國際上發現並相繼在《科學》《細胞》等雜誌上報導了核受體的非基因型作用機制及新型核受體藥物開發模式的,
原文連結:
原文摘要:
Retinoid X receptor-alpha (RXRα) binds to DNAeither as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a ‘three-pronged’ combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head–tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.
原文連結:
原文摘要:
Retinoid X receptor-alpha (RXRα) binds to DNAeither as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a ‘three-pronged’ combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head–tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.