当前位置：
X-MOL 学术
›
ACS Chem. Biol.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Targeted Disruption of Myc–Max Oncoprotein Complex by a Small Molecule
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-10-11 00:00:00 , DOI: 10.1021/acschembio.7b00799 Seung H. Choi 1 , Madhupriya Mahankali 2 , Sang Jun Lee 2 , Mitchell Hull 2 , H. Michael Petrassi 2 , Arnab K. Chatterjee 2 , Peter G. Schultz 2, 3 , Katherine A. Jones 1 , Weijun Shen 2
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-10-11 00:00:00 , DOI: 10.1021/acschembio.7b00799 Seung H. Choi 1 , Madhupriya Mahankali 2 , Sang Jun Lee 2 , Mitchell Hull 2 , H. Michael Petrassi 2 , Arnab K. Chatterjee 2 , Peter G. Schultz 2, 3 , Katherine A. Jones 1 , Weijun Shen 2
Affiliation
|
Myc plays important roles in cell cycle progression, cell growth, and stem cell self-renewal. Although dysregulation of Myc expression is a hallmark of human cancers, there is no Myc targeted therapy yet. Here, we report sAJM589, a novel small molecule Myc inhibitor, identified from a PCA-based high-throughput screen. sAJM589 potently disrupts the Myc–Max heterodimer in a dose dependent manner with an IC50 of 1.8 ± 0.03 μM. sAJM589 preferentially inhibits transcription of Myc target genes in a Burkitt lymphoma cell model, P493-6. Genome-wide transcriptome analysis showed that sAJM589 treatment and Myc depletion induced similar gene expression profiles. Consistently, sAJM589 suppressed cellular proliferation in diverse Myc-dependent cancer cell lines and anchorage independent growth of Raji cells. Disruption of the Myc–Max interaction by sAJM589 reduced Myc protein levels, possibly by promoting ubiquitination and degradation of Myc. Collectively, these results suggest that sAJM589 may be a basis for the development of potential inhibitors of Myc-dependent cell growth.
中文翻译：
小分子有针对性地破坏Myc-Max癌蛋白复合物。
Myc在细胞周期进程，细胞生长和干细胞自我更新中起重要作用。尽管Myc表达失调是人类癌症的标志，但尚无Myc靶向疗法。在这里，我们报告从基于PCA的高通量筛选中鉴定出的新型小分子Myc抑制剂sAJM589。sAJM589以剂量依赖性方式通过IC 50强力破坏Myc-Max异二聚体为1.8±0.03μM。sAJM589优先抑制Burkitt淋巴瘤细胞模型P493-6中Myc靶基因的转录。全基因组转录组分析显示sAJM589处理和Myc耗竭诱导相似的基因表达谱。一致地，sAJM589抑制了多种Myc依赖性癌细胞系中的细胞增殖以及Raji细胞的锚定非依赖性生长。sAJM589破坏Myc-Max相互作用降低了Myc蛋白水平，可能是通过促进泛素化和Myc降解。总体而言，这些结果表明，sAJM589可能是开发Myc依赖性细胞生长潜在抑制剂的基础。
更新日期：2017-10-11
中文翻译：
小分子有针对性地破坏Myc-Max癌蛋白复合物。
Myc在细胞周期进程，细胞生长和干细胞自我更新中起重要作用。尽管Myc表达失调是人类癌症的标志，但尚无Myc靶向疗法。在这里，我们报告从基于PCA的高通量筛选中鉴定出的新型小分子Myc抑制剂sAJM589。sAJM589以剂量依赖性方式通过IC 50强力破坏Myc-Max异二聚体为1.8±0.03μM。sAJM589优先抑制Burkitt淋巴瘤细胞模型P493-6中Myc靶基因的转录。全基因组转录组分析显示sAJM589处理和Myc耗竭诱导相似的基因表达谱。一致地，sAJM589抑制了多种Myc依赖性癌细胞系中的细胞增殖以及Raji细胞的锚定非依赖性生长。sAJM589破坏Myc-Max相互作用降低了Myc蛋白水平，可能是通过促进泛素化和Myc降解。总体而言，这些结果表明，sAJM589可能是开发Myc依赖性细胞生长潜在抑制剂的基础。
京公网安备 11010802027423号