MYC功能在癌症中的重要性是在1970年代后期发现的,当时确定了导致粒细胞白血病的禽逆转录病毒的序列。从那以后,40多年的不断研究强调了这种蛋白质在恶性转化中的重要性,尤其是血液病。的确,原癌基因的较高表达之间的一些最早的联系(如MYC),在伯基特淋巴瘤中进行了基因重排及其与癌症发展的关系,慢性粒细胞白血病和小鼠浆细胞瘤。多发性骨髓瘤(MM),特别是,是与MYC失调严格相关的浆细胞恶性肿瘤,这表明针对它的治疗策略将有益于治疗这种疾病。然而,瞄准MYC是-而且,不知何故,由于其独特的性质,仍然具有挑战性:缺乏明确的三维结构,核定位和缺乏可靶向的酶口袋。尽管有这些困难,然而,许多研究显示了直接或间接抑制MYC的潜在治疗效果.已经测试了不同的分子,事实上,在MM的背景下。在这次审查中,我们总结了不同化合物的现状,包括他们的临床试验结果,并建议继续努力确定,repurpose,重新设计或改进候选药物,将其与标准治疗相结合,以克服耐药性并更好地管理骨髓瘤治疗。
The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in particular, is a plasma cell malignancy strictly associated with MYC deregulation, suggesting that therapeutic strategies against it would be beneficial in treating this disease. However, targeting MYC was - and, somehow, still is - challenging due to its unique properties: lack of defined three-dimensional structure, nuclear localization and absence of a targetable enzymatic pocket. Despite these difficulties, however, many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition. Different molecules have been tested, in fact, in the context of MM. In this review, we summarize the current status of the different compounds, including the results of their clinical testing, and propose to continue with the efforts to identify, repurpose, redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.