Protein kinase inhibitors and epigenetic regulatory molecules are two main kinds of anticancer drugs developed in recent years. Both kinds of drugs harbor their own advantages and disadvantages in the treatment of cancer, and the development of small molecules which could target at kinases and epigenetic targets simultaneously can avoid the defects of drugs which only targets at kinases or epigenetic proteins. In this study, a series of 4,5-dihydro-[1,2,4]triazolo [4,3-f]pteridine derivatives were designed and synthesized based on the structure of PLK1 inhibitor BI-2536. Subsequent targets affinity screen and antiproliferative activity test led to the discovery of the most potent dual PLK1/BRD4 inhibitor 9b with good potency for both PLK1 (IC50 = 22 nM) and BRD4 (IC50 = 109 nM) as well as favorable antiproliferative activity against a panel of cancer cell lines. 9b could induce cell cycle arrest and apoptosis in acute myeloid leukemia cell line MV 4-11 in a concentration dependent manner. It could also downregulate the transcription of several proliferation-related oncogenes, including c-MYC, MYCN and BCL-2. Finally, in a MV4-11 mouse xenograft model, 9b exhibited favorable in vivo antitumor activity with 66% tumor growth inhibition (TGI) at a dose of 60 mg/kg while without obvious toxicity. This study thus provided us a start point for the development of new dual PLK1/BRD4 inhibitors as anticancer agents.

中文翻译：

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设计，合成和生物学评估4,5-二氢-[1,2,4]三唑并[4,3-f]蝶啶衍生物作为新型双重PLK1 / BRD4抑制剂。

蛋白激酶抑制剂和表观遗传调控分子是近年来开发的两种主要的抗癌药物。两种药物在治疗癌症方面都有其自身的优缺点，同时开发可同时靶向激酶和表观遗传学靶标的小分子可避免仅靶向激酶或表观遗传蛋白的药物缺陷。在这项研究中，基于PLK1抑制剂BI-2536的结构设计和合成了一系列4,5-二氢-[1,2,4]三唑并[4,3-f]蝶啶衍生物。随后的靶标亲和力筛选和抗增殖活性测试导致发现了最有效的双重PLK1 / BRD4抑制剂9b，对PLK1（IC50 = 22 nM）和BRD4（IC50 = 109 nM）都具有良好的效力，并且对甲壳素具有良好的抗增殖活性癌细胞系。9b可以浓度依赖性的方式诱导急性髓样白血病细胞株MV 4-11的细胞周期停滞和凋亡。它还可能下调几种与增殖有关的癌基因的转录，包括c-MYC，MYCN和BCL-2。最后，在MV4-11小鼠异种移植模型中，剂量为60 mg / kg的9b表现出良好的体内抗肿瘤活性和66％的肿瘤生长抑制（TGI），而没有明显的毒性。因此，这项研究为我们开发新的抗PLK1 / BRD4双重抑制剂提供了起点。