Institut de recherches cliniques de Montréal (IRCM), 110 Pine Ave W., Montréal, Québec, H2W 1R7, Canada.
Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada.
Eur J Med Chem. 2021 Mar 5;213:113137. doi: 10.1016/j.ejmech.2020.113137. Epub 2020 Dec 29.
The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed.
由于其在超过 50%的人类癌症中的异常激活，MYC 癌基因被认为是癌症患者临床干预的高度优先目标。由于其固有无序的性质以及缺乏结合位点和酶活性，直接的小分子抑制 MYC 一直受到阻碍。然而，近年来，随着蛋白质结构信息的出现和越来越多的可用于加速药物化学中命中到先导过程的计算工具的出现，出现了许多间接靶向 MYC 的策略。在这篇综述中，我们概述了为这些策略的临床应用开发的小分子，包括稳定 MYC 鸟嘌呤四联体、抑制 BET 因子 BRD4 以及破坏 MYC:MAX 异二聚体。还讨论了最近在蛋白质水平上发现的用于间接 MYC 抑制的新靶标。
