Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1).
Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1).
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DOI：
10.1002/cmdc.201500488
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发表时间：
2016-04-19
期刊：
影响因子：
3.4
通讯作者：
Howell LA
中科院分区：
文献类型：
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作者：
Beekman AM;O'Connell MA;Howell LA
蛋白质-蛋白质相互作用（PPIs）控制着癌症和肿瘤生长中的许多细胞过程。值得关注的是PPIs在调节细胞凋亡中的作用。抗凋亡调节蛋白Bcl - 2家族的过度表达在几种癌症中普遍存在，导致对放疗和化疗的耐药。在这个家族中，髓细胞白血病- 1 （Mcl - 1）已被证明是最难靶向的，也是导致治疗耐药的主要原因之一。利用凋亡调节蛋白Noxa和Mcl‐1之间的选择性PPI，利用荧光偏振测定，我们已经确定了四个具有调节Mcl‐1能力的小分子。对鉴定的化合物进行了计算建模，并与Mcl‐1结合界面对接，以获得有关其结合位点的结构信息，从而为未来的模拟设计奠定基础。当检测它们对过表达Mcl‐1的胰腺细胞系（MiaPaCa‐2和BxPC‐3）的活性时，鉴定的化合物显示出生长抑制，表明有效的Mcl‐1调节。
Protein–protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl‐2 family of proteins is commonly observed in several cancers, leading to resistance towards both radiation and chemotherapies. From this family, myeloid cell leukemia‐1 (Mcl‐1) has proven the most difficult to target, and one of the leading causes of treatment resistance. Exploiting the selective PPI between the apoptosis‐regulating protein Noxa and Mcl‐1, utilising a fluorescence polarization assay, we have identified four small molecules with the ability to modulate Mcl‐1. The identified compounds were computationally modelled and docked against the Mcl‐1 binding interface to obtain structural information about their binding sites allowing for future analogue design. When examined for their activity towards pancreatic cell lines that overexpress Mcl‐1 (MiaPaCa‐2 and BxPC‐3), the identified compounds demonstrated growth inhibition, suggesting effective Mcl‐1 modulation.