Discovery of methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate, an improved small-molecule inhibitor of c-Myc-max dimerization.
Discovery of methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate, an improved small-molecule inhibitor of c-Myc-max dimerization.
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DOI：
10.1002/cmdc.201402189
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发表时间：
2014-10
期刊：
影响因子：
3.4
通讯作者：
Fletcher, Steven
中科院分区：
文献类型：
--
作者：
Chauhan, Jay;Wang, Huabo;Yap, Jeremy L.;Sabato, Philip E.;Hu, Angela;Prochownik, Edward V.;Fletcher, Steven
c-Myc是一种bHLH-ZIP转录因子，负责多种靶基因的转录，参与许多与癌症相关的细胞过程，如增殖、分化、凋亡和代谢。c-Myc的过度表达已被观察到，并直接导致了多种人类癌症，包括造血系统、肺癌、前列腺癌和结肠癌。为了具有转录活性，c-Myc必须首先通过其自身的bHLH-ZIP结构域与Max二聚化。一种已证实的抑制c-Myc致癌活性的策略是干扰c-Myc - max异源二聚体的结构完整性。小分子10074-G5是一种c-Myc - max二聚化抑制剂（IC50 = 146 μM），通过结合和稳定单体形式的c-Myc起作用。在此，我们报告了我们正在进行的努力，以优化10074- g5相关分子在体外和过度表达c-Myc的癌细胞中的c-Myc - max抑制活性。具体来说，我们已经鉴定出10074-G5的同源物，称为3jc48-3，其抑制c-Myc-Max二聚化的效力是母体化合物的5倍（IC50 = 34 μM）。此外，3jc48-3对c-Myc - max异源二聚体的选择性约为Max-Max二聚体的两倍，这表明，与它的前身一样，它的作用方式是通过结合c-Myc。3jc48-3通过在G0/G1期引起生长停滞，抑制过表达c- myc的HL60和Daudi细胞的增殖，IC50值为个位数微摩尔。此外，共免疫沉淀研究表明，3jc48-3抑制细胞中c-Myc-Max二聚化，这进一步被c- myc驱动的荧光素酶报告基因的特异性沉默所证实。最后，与之前描述的10074-G5类似物不同，10074-G5在摄取后会迅速释放和/或被细胞代谢，3jc48-3的细胞内半衰期为1017小时。总的来说，这些数据表明3jc48-3是迄今为止报道的最有效的细胞活性c-Myc抑制剂之一。
c-Myc is a bHLH-ZIP transcription factor that is responsible for the transcription of a wide range of target genes involved in many cancer-related cellular processes, such as proliferation, differentiation, apoptosis and metabolism. Over-expression of c-Myc has been observed in, and directly contributes to, a variety of human cancers including those of the hematopoietic system, lung, prostate and colon. To become transcriptionally active, c-Myc must first dimerize with Max via its own bHLH-ZIP domain. A proven strategy towards the inhibition of c-Myc oncogenic activity is to interfere with the structural integrity of the c-Myc–Max heterodimer. The small-molecule 10074-G5 is an inhibitor of c-Myc–Max dimerization (IC50 = 146 μM) that operates by binding and stabilizing c-Myc in its monomeric form. Herein, we report on our on-going efforts to optimize the c-Myc–Max inhibitory activity of 10074-G5-related molecules in vitro and in cancer cells that over-express c-Myc. Specifically, we have identified a congener of 10074-G5, termed 3jc48-3, that is about five times as potent (IC50 = 34 μM) at inhibiting c-Myc–Max dimerization as the parent compound. In addition, 3jc48-3 exhibited an approximate two-fold selectivity for c-Myc–Max heterodimers over Max–Max dimers, suggesting that, like its predecessor, its mode of action is through binding c-Myc. 3jc48-3 inhibited the proliferation of c-Myc-over-expressing HL60 and Daudi cells with single-digit micromolar IC50 values by causing growth arrest at the G0/G1 phase. Furthermore, co-immunoprecipitation studies indicated that 3jc48-3 inhibits c-Myc–Max dimerization in cells, which was further substantiated by the specific silencing of a c-Myc-driven luciferase reporter gene. Finally, unlike previously described 10074-G5 analogues, which are rapidly released and/or metabolized by cells following their uptake, 3jc48-3’s intracellular half-life was >17 h. Collectively, these data demonstrate 3jc48-3 to be one of the most potent cellularly active c-Myc inhibitors reported to date.
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影响因子：
1.8
作者：
Jung, Michael E.;Dong, Timothy A.;Cai, Xiaolu
通讯作者：
Cai, Xiaolu
影响因子：
64.5
作者：
Matzuk MM;McKeown MR;Filippakopoulos P;Li Q;Ma L;Agno JE;Lemieux ME;Picaud S;Yu RN;Qi J;Knapp S;Bradner JE
通讯作者：
Bradner JE
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
--
作者：
Kiessling, Anke;Sperl, Bianca;Berg, Thorsten
通讯作者：
Berg, Thorsten
DOI：
10.1124/jpet.110.170555
发表时间：
2010-12-01
影响因子：
3.5
作者：
Clausen, Dana M.;Guo, Jianxia;Eiseman, Julie L.
通讯作者：
Eiseman, Julie L.