針對幾種常見癌癥的化療治療研究發(fā)現(xiàn)，一種特殊的蛋白質可能是導致患者對化療藥物產(chǎn)生耐藥性的關鍵分子,。在這一發(fā)現(xiàn)基礎上,，科研人員有望找到改善癌癥化療效果的新方法。
來自美國達納－法伯癌癥研究所的研究人員20日在英國《自然－化學生物學》雜志網(wǎng)絡版上介紹說,，在參與控制細胞凋亡（即細胞的程序性死亡）的蛋白質中,，有的蛋白質負責破壞細胞，有的則負責幫助細胞存活,，兩者達到一種動態(tài)平衡,。MCL－1蛋白質屬于后者。
在針對白血病,、淋巴癌,、乳腺癌等多種常見癌癥的化療研究中，他們發(fā)現(xiàn),，MCL－1發(fā)揮著幫助腫瘤細胞“躲”過藥物攻擊繼續(xù)生長的關鍵作用,。
研究人員說，腫瘤細胞同時也會使MCL－1等有利于其生長的蛋白質過度表達,，從而使得化療藥物效力大打折扣,。在這一研究基礎上，他們研發(fā)了MCL－1抑制劑類的試驗藥物,，正在進行動物實驗,。他們希望MCL－1抑制劑能夠阻斷該蛋白質的活性，從而避免腫瘤細胞對化療藥物產(chǎn)生耐藥性,，達到更好的化療效果,。(生物谷Bioon.net)
生物谷推薦原文出處：
Nature Chemical Biology doi:10.1038/nchembio.391
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer
Michelle L Stewart1,2, Emiko Fire3, Amy E Keating3 & Loren D Walensky1,2
The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1–specific agent that defines the structural and functional features of targeted MCL-1 inhibition.
