Structure-based inhibitor design of mutant RAS proteins-a paradigm shift.
Structure-based inhibitor design of mutant RAS proteins-a paradigm shift.
复制标题
突变Ras蛋白的基于结构的抑制剂设计 - A范式转移。
DOI：
10.1007/s10555-020-09914-6
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Vértessy BG
中科院分区：
文献类型：
--
作者：
Nyíri K;Koppány G;Vértessy BG
KRAS蛋白是小分子GTP酶家族的一员，是包括细胞增殖在内的多种细胞活动的重要生理调节因子。然而，KRAS突变存在于多种癌症类型中，最常见的是胰腺癌(>； 60%)、结直肠癌(>； 40%)和肺癌，通过过度激活增殖来推动肿瘤发生过程。在这些类型的恶性肿瘤中，KRAS蛋白的G12C突变尤其丰富。尽管KRAS在人类疾病中至关重要，但很长一段时间以来，KRAS被认为是不可药物的，因为除了核苷酸结合位点外，KRAS似乎缺乏潜在的药物结合口袋，由于KRAS对GDP和GTP都有很高的亲和力，因此很难成为靶点。最近，一种新的方法打破了僵局，并提供了证据表明，在共价靶向G12C突变体KRAS时，揭示了一个高度动态的口袋。这种新的靶向特别重要，因为它为药物选择性提供了固有的解决方案。基于这些结果，各种基于结构的药物设计项目已经启动，以开发选择性KRAS突变抑制剂。除了主要适用于G12C突变的共价修饰策略外，对于其他频繁发生的致癌G12突变，也提出了不同的创新解决方案。在这里，我们总结了这一领域的最新进展，为新的方法提供了展望，并强调了KRAS的特殊性质，这可能会带来一些新的挑战。本文的在线版本(10.1007/s10555-02020-6)包含向授权用户提供的补充材料。
As a member of small GTPase family, KRAS protein is a key physiological modulator of various cellular activities including proliferation. However, mutations of KRAS present in numerous cancer types, most frequently in pancreatic (> 60%), colorectal (> 40%), and lung cancers, drive oncogenic processes through overactivation of proliferation. The G12C mutation of KRAS protein is especially abundant in the case of these types of malignancies. Despite its key importance in human disease, KRAS was assumed to be non-druggable for a long time since the protein seemingly lacks potential drug-binding pockets except the nucleotide-binding site, which is difficult to be targeted due to the high affinity of KRAS for both GDP and GTP. Recently, a new approach broke the ice and provided evidence that upon covalent targeting of the G12C mutant KRAS, a highly dynamic pocket was revealed. This novel targeting is especially important since it serves with an inherent solution for drug selectivity. Based on these results, various structure-based drug design projects have been launched to develop selective KRAS mutant inhibitors. In addition to the covalent modification strategy mostly applicable for G12C mutation, different innovative solutions have been suggested for the other frequently occurring oncogenic G12 mutants. Here we summarize the latest advances of this field, provide perspectives for novel approaches, and highlight the special properties of KRAS, which might issue some new challenges. The online version of this article (10.1007/s10555-020-09914-6) contains supplementary material, which is available to authorized users.
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作者：
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DOI：
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发表时间：
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影响因子：
11.1
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