During the last two decades, the study of Mcl-1, an anti-apoptotic member of the Bcl-2 family, attracted researchers due to its important role in cancer cell survival and tumor development. The significance of Mcl-1 protein in resistance to chemotherapeutics makes it an attractive target in cancer therapy. Here, we discuss the diverse possibilities for indirect Mcl-1 inhibition through its downregulation, for example, via targeting for proteasomal degradation or blockage of translation and transcription. We also provide an overview of the direct blocking of protein-protein interactions with pro-apoptotic Bcl-2 family proteins, including examples of the most promising regulators of Mcl-1 and selective BH3-mimetics, which at present are under clinical evaluation. Moreover, several approaches for the co-targeting of Mcl-1 and other proteins (e.g., CDKs) are also presented. In addition, we highlight the broad spectrum of problems that accompanied the discovery and development of effective Mcl-1 inhibitors.

中文翻译：

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Mcl-1是癌症治疗的“障碍”：我们现在可以针对它吗？

在过去的二十年中，Bcl-2家族抗凋亡成员Mcl-1的研究由于其在癌细胞存活和肿瘤发展中的重要作用而吸引了研究人员。Mcl-1蛋白在对化学疗法的抗性中具有重要意义，使其成为癌症治疗中有吸引力的靶标。在这里，我们讨论了通过下调间接抑制Mcl-1的各种可能性，例如通过靶向蛋白酶体降解或翻译和转录的阻断。我们还概述了与促凋亡Bcl-2家族蛋白直接相互作用的蛋白-蛋白相互作用，包括最有前途的Mcl-1调节剂和选择性BH3-模拟物的实例，目前正在临床评估中。此外，几种共同靶向Mcl-1和其他蛋白质的方法（例如，CDKs）。此外，我们重点介绍了伴随有效Mcl-1抑制剂的发现和开发而产生的广泛问题。