Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Curr Top Med Chem. 2011;11(3):258-80. doi: 10.2174/156802611794072614.
Between 40,000 and 200,000 protein-protein interactions have been predicted to exist within the human interactome. As these interactions are of a critical nature in many important cellular functions and their dysregulation is causal of disease, the modulation of these binding events has emerged as a leading, yet difficult therapeutic arena. In particular, the targeting of protein-protein interactions relevant to cancer is of fundamental importance as the tumor-promoting function of several aberrantly expressed proteins in the cancerous state is directly resultant of its ability to interact with a protein-binding partner. Of significance, these protein complexes play a crucial role in each of the steps of the central dogma of molecular biology, the fundamental processes of genetic transmission. With the many important discoveries being made regarding the mechanisms of these genetic process, the identification of new chemical probes are needed to better understand and validate the druggability of protein-protein interactions related to the central dogma. In this review, we provide an overview of current small molecule-based protein-protein interaction inhibitors for each stage of the central dogma: transcription, mRNA splicing and translation. Importantly, through our analysis we have uncovered a lack of necessary probes targeting mRNA splicing and translation, thus, opening up the possibility for expansion of these fields.
在人类互作组中，据预测存在着 4 万到 20 万种蛋白质-蛋白质相互作用。由于这些相互作用对许多重要的细胞功能具有关键性质，并且它们的失调是疾病的原因，因此这些结合事件的调节已成为一个主要但困难的治疗领域。特别是，针对与癌症相关的蛋白质-蛋白质相互作用的靶向治疗具有重要意义，因为在癌症状态下，几种异常表达的蛋白质的肿瘤促进功能直接源自其与蛋白质结合伴侣相互作用的能力。值得注意的是，这些蛋白质复合物在分子生物学中心法则的每一个步骤中都起着至关重要的作用，是遗传传递的基本过程。随着关于这些遗传过程机制的许多重要发现，需要识别新的化学探针，以更好地了解和验证与中心法则相关的蛋白质-蛋白质相互作用的可药性。在这篇综述中，我们概述了当前基于小分子的蛋白质-蛋白质相互作用抑制剂在中心法则的各个阶段：转录、mRNA 剪接和翻译。重要的是，通过我们的分析，我们发现针对 mRNA 剪接和翻译的必要探针缺乏，因此，为这些领域的扩展开辟了可能性。
