Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-02 DOI:10.1016/j.bioorg.2024.107929
Kai Ran, Yong Li, Yi-Mei Zhang, Dian-Yong Tang, Zhong-Zhu Chen, Zhi-Gang Xu, Li Zhang, Bo-Chu Wang, Jiu-Hong Huang
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引用次数: 0

Abstract

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC50 values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC50 value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of cancer therapy.

发现和优化新型 4-吗啉基噻吩并[3,2-d]嘧啶衍生物,作为癌症治疗的强效 BET 抑制剂。
鉴定结构新颖、活性强的 BET 抑制剂是抗癌治疗领域的一大进步。在本研究中,我们利用之前的筛选工作成果,成功优化并合成了一系列具有 4-吗啉基噻吩并[3,2-d]嘧啶结构的新型溴代端外 (BET) 抑制剂。在合成的化合物中,化合物 6c 是一个很有希望的候选化合物,它对各种 BET 异构体蛋白都表现出卓越的抑制活性,IC50 值从 3.3 到 42.0 nM 不等。在细胞实验中,化合物 6c 在 SU-DHL-4 细胞中表现出强大的抗增殖作用,IC50 值为 8.6 ± 3.3 nM。进一步的机理研究发现,化合物 6c 能有效降低受 BET 蛋白调控的关键致癌驱动因子 c-Myc 的表达,并以剂量依赖性的方式诱导细胞周期停滞在 G1 期以及细胞凋亡。此外,通过对化合物 6c 的生理化学性质和药代动力学性质进行硅学预测,发现该化合物具有可接受的类药物特性。综合这些发现,化合物 6c 是一种新型、强效的 BET 抑制剂,因此有望在癌症治疗领域进行后续的临床前评估。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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