Division of Medical Genomics and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Institute of Genetics, Zhejiang University and Department of Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
Signal Transduct Target Ther. 2021 Mar 10;6(1):117. doi: 10.1038/s41392-021-00500-y.
The Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its "undruggable" properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.
Myc 原癌基因家族由三个成员组成，分别是 C-MYC、MYCN 和 MYCL，它们分别编码转录因子 c-Myc（以下简称 Myc）、N-Myc 和 L-Myc。Myc 蛋白协调多种生理过程，包括细胞增殖、分化、存活和凋亡。Myc 调节约 15%的全基因组转录组，其失调重排肿瘤细胞内的细胞信号模块，从而获得选择性优势。Myc 的失调发生在超过 70%的人类癌症中，并与预后不良相关；因此，高活性 Myc 癌蛋白被提出作为数十年来的理想药物靶点。然而，目前尚无专门针对 Myc 的特定药物，主要是因为它具有“不可成药”的特性：缺乏常规小分子结合的酶口袋；由于 Myc 主要定位于细胞核，抗体无法接近。尽管靶向 Myc 的主题在过去几十年中得到了积极的综述，但该领域的新进展不断涌现。在这篇综述中，在对 Myc 驱动的癌症潜在可成药靶点的有价值的来源进行全面总结之后，我们还深入探讨了利用巨胞饮作用将类似 Omomyc 的肽或抗体剂递送至细胞内区室以进行癌症治疗的有希望的未来。
