文章：

3JC48-3（甲基4′-甲基-5-（7-硝基苯[c][1,2,5]恶二唑-4-基）-[1,1′-联苯]-3-羧酸盐）：一种新型MYC/MAX

3JC48-3 (methyl 4′-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1′-biphenyl]-3-carboxylate): a novel MYC/MAX 

原文发布日期：2022-04-19 

英文摘要：

The proto-oncogene cellular myelocytomatosis (c-Myc) is a transcription factor that is upregulated in several human cancers. Therapeutic targeting of c-Myc remains a challenge because of a disordered protein tertiary structure. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MYC-associated factor X (MAX) to function as a transcription factor. An attractive strategy is to inhibit MYC/MAX dimerization to decrease c-Myc transcriptional function. Several methods have been described to inhibit MYC/MAX dimerization including small molecular inhibitors and proteomimetics. We studied the effect of a second-generation small molecular inhibitor 3JC48-3 on prostate cancer growth and viability. In our experimental studies, we found 3JC48-3 decreases prostate cancer cells’ growth and viability in a dose-dependent fashion in vitro. We confirmed inhibition of MYC/MAX dimerization by 3JC48-3 using immunoprecipitation experiments. We have previously shown that the MYC/MAX heterodimer is a transcriptional repressor of a novel kinase protein kinase D1 (PrKD1). Treatment with 3JC48-3 upregulated PrKD1 expression and phosphorylation of known PrKD1 substrates: the threonine 120 (Thr-120) residue in beta-catenin and the serine 216 (Ser-216) in Cell Division Cycle 25 (CDC25C). The mining of gene expression in human metastatic prostate cancer samples demonstrated an inverse correlation between PrKD1 and c-Myc expression. Normal mice and mice with patient-derived prostate cancer xenografts (PDX) tolerated intraperitoneal injections of 3JC48-3 up to 100 mg/kg body weight without dose-limiting toxicity. Preliminary results in these PDX mouse models suggest that 3JC48-3 may be effective in decreasing the rate of tumor growth. In conclusion, our study demonstrates that 3JC48-3 is a potent MYC/MAX heterodimerization inhibitor that decreases prostate cancer growth and viability associated with upregulation of PrKD1 expression and kinase activity. 

摘要翻译： 

原癌基因细胞髓细胞瘤病（c-Myc）是一种在多种人类癌症中表达上调的转录因子。由于蛋白质三级结构无序，c-Myc的治疗靶向仍面临挑战。c-Myc的碱性螺旋结构和拉链蛋白需与其伴侣MYC相关因子X（MAX）形成专性异源二聚体才能发挥转录因子功能。抑制MYC/MAX二聚化以降低c-Myc转录功能是一种具有吸引力的策略。目前已有多种方法被报道用于抑制MYC/MAX二聚化，包括小分子抑制剂和蛋白质模拟物。我们研究了第二代小分子抑制剂3JC48-3对前列腺癌生长和存活力的影响。实验研究发现，3JC48-3在体外以前剂量依赖方式降低前列腺癌细胞的生长和存活力。通过免疫共沉淀实验，我们证实3JC48-3可抑制MYC/MAX二聚化。我们既往研究表明MYC/MAX异源二聚体是新型激酶蛋白激酶D1（PrKD1）的转录抑制因子。3JC48-3处理可上调PrKD1表达及其已知底物的磷酸化水平：β-连环蛋白的苏氨酸120位点（Thr-120）和细胞分裂周期25（CDC25C）的丝氨酸216位点（Ser-216）。对人类转移性前列腺癌样本的基因表达分析显示，PrKD1与c-Myc表达呈负相关。正常小鼠和携带患者来源前列腺癌异种移植（PDX）的小鼠对高达100 mg/kg体重的3JC48-3腹腔注射耐受良好，未出现剂量限制性毒性。PDX小鼠模型的初步结果表明，3JC48-3或能有效降低肿瘤生长速率。本研究证实，3JC48-3是一种有效的MYC/MAX异源二聚化抑制剂，可通过上调PrKD1表达和激酶活性来抑制前列腺癌生长和存活。

原文链接：

3JC48-3 (methyl 4′-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1′-biphenyl]-3-carboxylate): a novel MYC/MAX