針對(duì)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(zhì)可能是導(dǎo)致患者對(duì)化療藥物產(chǎn)生耐藥性的關(guān)鍵分子,。在這一發(fā)現(xiàn)基礎(chǔ)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(dá)納－法伯癌癥研究所的研究人員20日在英國《自然－化學(xué)生物學(xué)》雜志網(wǎng)絡(luò)版上介紹說,，在參與控制細(xì)胞凋亡（即細(xì)胞的程序性死亡）的蛋白質(zhì)中,，有的蛋白質(zhì)負(fù)責(zé)破壞細(xì)胞,，有的則負(fù)責(zé)幫助細(xì)胞存活，兩者達(dá)到一種動(dòng)態(tài)平衡,。MCL－1蛋白質(zhì)屬于后者,。
在針對(duì)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(xì)胞“躲”過藥物攻擊繼續(xù)生長的關(guān)鍵作用,。
研究人員說,，腫瘤細(xì)胞同時(shí)也會(huì)使MCL－1等有利于其生長的蛋白質(zhì)過度表達(dá)，從而使得化療藥物效力大打折扣,。在這一研究基礎(chǔ)上,，他們研發(fā)了MCL－1抑制劑類的試驗(yàn)藥物，正在進(jìn)行動(dòng)物實(shí)驗(yàn),。他們希望MCL－1抑制劑能夠阻斷該蛋白質(zhì)的活性,，從而避免腫瘤細(xì)胞對(duì)化療藥物產(chǎn)生耐藥性，達(dá)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.
