A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells.
A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells.
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DOI：
10.1039/c3sc50481f
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发表时间：
2013-08-01
期刊：
影响因子：
8.4
通讯作者：
Tavassoli A
中科院分区：
文献类型：
--
作者：
Birts CN;Nijjar SK;Mardle CA;Hoakwie F;Duriez PJ;Blaydes JP;Tavassoli A
识别转录因子蛋白质-蛋白质相互作用的直接调节剂是配体发现的关键挑战，有望显着推进目前的癌症治疗方法。在这里，我们报告的C-末端结合蛋白（CtBP）转录抑制剂，通过筛选高达64万成员的遗传编码的环肽库确定的NADH依赖性二聚化的抑制剂。CtBP二聚体形成与多个基因的表观遗传调控相关的转录复合物的核心，所述多个基因控制癌细胞的许多特征，包括增殖、存活和迁移。CtBP单体也具有独特和关键的细胞功能，因此目前的实验工具，耗尽所有形式的靶蛋白（如siRNA）不允许这种代谢调节的转录因子的细胞后果被破译。来自我们筛选的最有效的抑制剂（环-SGWTVVRMY）被证明在体外和细胞中破坏CtBP二聚化。该化合物用作化学工具，以确定CtBP的NADH依赖性二聚化调节癌细胞中有丝分裂保真度的维持。用所鉴定的抑制剂处理高度糖酵解的乳腺癌细胞系显著降低了它们的有丝分裂保真度、增殖和集落形成潜力，而该化合物不影响具有较低糖酵解通量的细胞的有丝分裂保真度。这项工作不仅将转化细胞的代谢状态改变与肿瘤细胞表型的关键决定因素联系起来，而且未被发现的化合物还可以作为开发潜在治疗剂的起点，这些治疗剂通过破坏CtBP染色质修饰复合物来靶向肿瘤。
Identification of direct modulators of transcription factor protein–protein interactions is a key challenge for ligand discovery that promises to significantly advance current approaches to cancer therapy. Here, we report an inhibitor of NADH-dependent dimerization of the C-terminal binding protein (CtBP) transcriptional repressor, identified by screening genetically encoded cyclic peptide libraries of up to 64 million members. CtBP dimers form the core of transcription complexes associated with epigenetic regulation of multiple genes that control many characteristics of cancer cells, including proliferation, survival and migration. CtBP monomers also have distinct and critical cellular function, thus current experimental tools that deplete all forms of a targeted protein (e.g. siRNA) do not allow the cellular consequences of this metabolically regulated transcription factor to be deciphered. The most potent inhibitor from our screen (cyclo-SGWTVVRMY) is demonstrated to disrupt CtBP dimerization in vitro and in cells. This compound is used as a chemical tool to establish that the NADH-dependent dimerization of CtBPs regulates the maintenance of mitotic fidelity in cancer cells. Treatment of highly glycolytic breast cancer cell lines with the identified inhibitor significantly reduced their mitotic fidelity, proliferation and colony forming potential, whereas the compound does not affect mitotic fidelity of cells with lower glycolytic flux. This work not only links the altered metabolic state of transformed cells to a key determinant of the tumor cell phenotype, but the uncovered compound also serves as the starting point for the development of potential therapeutic agents that target tumors by disrupting the CtBP chromatin-modifying complex.
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DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8
作者：
Birts, C. N.;Bergman, L. M.;Blaydes, J. P.
通讯作者：
Blaydes, J. P.
影响因子：
--
作者：
Bergman LM;Morris L;Darley M;Mirnezami AH;Gunatilake SC;Blaydes JP
通讯作者：
Blaydes JP
影响因子：
5.3
作者：
Hildebrand, JD;Soriano, P
通讯作者：
Soriano, P
DOI：
10.1073/pnas.1633591100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Fjeld, CC;Birdsong, WT;Goodman, RH
通讯作者：
Goodman, RH