拉伸伊马替尼的结构包膜,通过调节APP的β和γ分泌酶裂解减少β淀粉样蛋白的产生。

IF 3.8 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY
Frontiers in Chemistry Pub Date : 2024-10-08 eCollection Date: 2024-01-01 DOI:10.3389/fchem.2024.1381205
William J Netzer, Anjana Sinha, Mondana Ghias, Emily Chang, Katherina Gindinova, Emily Mui, Ji-Seon Seo, Subhash C Sinha
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引用次数: 0

摘要

我们以前曾发现,抗癌药物甲磺酸伊马替尼(IMT,商品名:格列卫)和化学性质不同的化合物 DV2-103(强效 Abl 和 Src 激酶抑制剂 PD173955 的激酶活性衍生物)可降低 Aβ 水平:格列卫)和一种化学性质不同的化合物 DV2-103(强效 Abl 和 Src 激酶抑制剂 PD173955 的一种激酶活性衍生物)主要通过一种溶酶体依赖性机制在低微摩尔浓度下降低 Aβ 水平,这种机制使 APP 更不易被 BACE1 蛋白分解,而不会直接抑制 BACE1 的酶活性,也不会广泛抑制其他 BACE1 底物的加工。此外,IMT 还能间接抑制γ-分泌酶并刺激自噬,从而通过多种途径降低 Aβ 的水平。在最近的两项研究中,我们证实了 IMT 和 DV2-103 的衍生物对 APP 代谢的类似影响。在本研究中,我们合成并测试了与 IMT 具有中等结构相似性的截然不同的 IMT 异构体(IMTi's)。与结构相似性无关的是,这些异构体在改变 APP 代谢方面表现出截然不同的效力。这将使我们能够选择最有效的异构体进行进一步衍生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Stretching the structural envelope of imatinib to reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP.

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.

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来源期刊
Frontiers in Chemistry
Frontiers in Chemistry Chemistry-General Chemistry
CiteScore
8.50
自引率
3.60%
发文量
1540
审稿时长
12 weeks
期刊介绍: Frontiers in Chemistry is a high visiblity and quality journal, publishing rigorously peer-reviewed research across the chemical sciences. Field Chief Editor Steve Suib at the University of Connecticut is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to academics, industry leaders and the public worldwide. Chemistry is a branch of science that is linked to all other main fields of research. The omnipresence of Chemistry is apparent in our everyday lives from the electronic devices that we all use to communicate, to foods we eat, to our health and well-being, to the different forms of energy that we use. While there are many subtopics and specialties of Chemistry, the fundamental link in all these areas is how atoms, ions, and molecules come together and come apart in what some have come to call the “dance of life”. All specialty sections of Frontiers in Chemistry are open-access with the goal of publishing outstanding research publications, review articles, commentaries, and ideas about various aspects of Chemistry. The past forms of publication often have specific subdisciplines, most commonly of analytical, inorganic, organic and physical chemistries, but these days those lines and boxes are quite blurry and the silos of those disciplines appear to be eroding. Chemistry is important to both fundamental and applied areas of research and manufacturing, and indeed the outlines of academic versus industrial research are also often artificial. Collaborative research across all specialty areas of Chemistry is highly encouraged and supported as we move forward. These are exciting times and the field of Chemistry is an important and significant contributor to our collective knowledge.
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