RT：研究发现与抗癌药物耐药性有关的蛋白质

研究发现与抗癌药物耐药性有关的蛋白质
美国科学家针对几种常见癌症的化疗治疗研究发现，一种特殊的蛋白质可能是导致患者对化疗药物产生耐药性的关键分子。在这一发现基础上，科研人员有望找到改善癌症化疗效果的新方法。
来自美国达纳－法伯癌症研究所的研究人员6月20日在英国《自然—化学生物学》（Nature Chemical Biology）杂志网络版上介绍说，在参与控制细胞凋亡（即细胞的程序性死亡）的蛋白质中，有的蛋白质负责破坏细胞，有的则负责帮助细胞存活，两者达到一种动态平衡。MCL-1蛋白质属于后者。
在针对白血病、淋巴癌、乳腺癌等多种常见癌症的化疗研究中，他们发现，MCL-1发挥着帮助肿瘤细胞“躲”过药物攻击继续生长的关键作用。
研究人员说，肿瘤细胞同时也会使MCL-1等有利于其生长的蛋白质过度表达，从而使得化疗药物效力大打折扣。在这一研究基础上，他们研发了MCL-1抑制剂类的试验药物，正在进行动物实验。他们希望MCL-1抑制剂能够阻断该蛋白质的活性，从而避免肿瘤细胞对化疗药物产生耐药性，达到更好的化疗效果。
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.