Covalent targeting of acquired cysteines in cancer.
Covalent targeting of acquired cysteines in cancer.
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DOI：
10.1016/j.cbpa.2015.11.004
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发表时间：
2016-02
影响因子：
7.8
通讯作者：
Dansen TB
中科院分区：
文献类型：
--
作者：
Visscher M;Arkin MR;Dansen TB
半胱氨酸的硫醇侧链具有独特的功能，药物猎人和化学生物学家已经开始开发。例如，用巯基反应性分子靶向激酶ATP结合口袋中的半胱氨酸残基，可以提高药物的选择性和效力，如抑制致癌基因BTK的伊马替尼，以及靶向致癌突变EGFR的CO-1686和AZD 9291。最近，二硫键文库和靶向GDP模拟物已被用于选择性标记KRAS中的G12 C致癌突变。我们推断其他癌基因也含有半胱氨酸突变，因此在《癌症体细胞突变目录》中筛选了经常获得的半胱氨酸。在这里，我们描述了最常见的突变，并讨论了这些突变如何成为半胱氨酸定向个性化治疗的潜在靶点。
The thiolate side chain of cysteine has a unique functionality that drug hunters and chemical biologists have begun to exploit. For example, targeting cysteine residues in the ATP-binding pockets of kinases with thiol-reactive molecules has afforded increased selectivity and potency to drugs like imbrutinib, which inhibits the oncogene BTK, and CO-1686 and AZD9291 that target oncogenic mutant EGFR. Recently, disulfide libraries and targeted GDP-mimetics have been used to selectively label the G12C oncogenic mutation in KRAS. We reasoned that other oncogenes contain mutations to cysteine, and thus screened the Catalog Of Somatic Mutations In Cancer for frequently acquired cysteines. Here, we describe the most common mutations and discuss how these mutations could be potential targets for cysteine-directed personalized therapeutics.