Discovery of novel Macrocyclic small molecules Based on 2-Amino-4-thiazolylpyridineas selective EGFR inhibitors with high Blood-Brain barrier penetration for the treatment of glioblastoma.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-23 DOI:10.1016/j.bioorg.2024.107905
Guowu Wu, Mingfeng Zhou, Fengqiu Guo, Yong Lin, Yongxin Chen, Yifan Kong, Jun Xiao, Shanhe Wan, Zhonghuang Li, Xiaoyun Wu, Tingting Zhang, Jiajie Zhang
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Abstract

Because epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene in glioblastoma (GBM), the development of EGFR inhibitors has become a promising direction for the treatment of GBM. However, due to factors such as limited blood-brain barrier (BBB) permeability and pathway compensation mechanisms, current EGFR inhibitors targeting GBM are not satisfactory. In the previous study, we obtained compound 10c with strong anti-cell proliferation activity. Since macrocyclization can effectively change the physical and chemical properties of molecules, and optimize their selectivity. Therefore, a series of 2-amino-4-thiazolyl pyridine scaffold macrocyclic derivatives were designed and synthesized using compound 10c as the lead compound in this study. Compound 3a, which inhibited the growth of glioblastoma cell lines U87MG and U87-EGFRVIII, had average IC50 values of 4.69 µM and 4.98 µM, respectively. Compound 3a was highly selective to 9 kinases in the ErbB family, including ErbB2 and ErbB4. In addition, compound 3a demonstrated good blood-brain barrier permeability in mice, the blood-brain concentration of the drug remained above 20 % within 5-60 min following intravenous administration in mice. In conclusion, compound 3a is a promising candidate for novel EGFR inhibitors targeting GBM.

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发现基于 2-Amino-4-thiazolylpyridine 的新型大环小分子,作为具有高血脑屏障渗透性的表皮生长因子受体选择性抑制剂,用于治疗胶质母细胞瘤。
由于表皮生长因子受体(EGFR)是胶质母细胞瘤(GBM)中最常见的突变癌基因,因此开发EGFR抑制剂已成为治疗GBM的一个前景广阔的方向。然而,受限于血脑屏障(BBB)通透性和通路补偿机制等因素,目前针对GBM的表皮生长因子受体抑制剂效果并不理想。在之前的研究中,我们获得了具有较强抗细胞增殖活性的化合物 10c。由于大环化可以有效改变分子的物理和化学性质,优化其选择性。因此,本研究以化合物 10c 为先导化合物,设计并合成了一系列 2-氨基-4-噻唑基吡啶支架大环衍生物。化合物 3a 可抑制胶质母细胞瘤细胞系 U87MG 和 U87-EGFRVIII 的生长,其平均 IC50 值分别为 4.69 µM 和 4.98 µM。化合物 3a 对 ErbB 家族的 9 种激酶(包括 ErbB2 和 ErbB4)具有高度选择性。此外,化合物 3a 在小鼠体内表现出良好的血脑屏障通透性,小鼠静脉注射后 5-60 分钟内血脑屏障药物浓度保持在 20% 以上。总之,化合物 3a 是针对 GBM 的新型表皮生长因子受体抑制剂的有望候选化合物。
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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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