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靶向脂质-蛋白相互作用治疗 Syk 介导的急性髓系白血病。

Targeting lipid-protein interaction to treat Syk-mediated acute myeloid leukemia.

机构信息

Department of Chemistry, University of Illinois Chicago (UIC), Chicago, IL, USA.

NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.

出版信息

Nat Chem Biol. 2023 Feb;19(2):239-250. doi: 10.1038/s41589-022-01150-z. Epub 2022 Oct 13.

DOI:10.1038/s41589-022-01150-z
PMID:36229686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9898191/
Abstract

Membrane lipids control the cellular activity of kinases containing the Src homology 2 (SH2) domain through direct lipid-SH2 domain interactions. Here we report development of new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction that block the cellular activity of their host proteins. As a pilot study, we evaluated the efficacy of lipid-SH2 domain interaction inhibitors for spleen tyrosine kinase (Syk), which is implicated in hematopoietic malignancies, including acute myeloid leukemia (AML). An optimized inhibitor (WC36) specifically and potently suppressed oncogenic activities of Syk in AML cell lines and patient-derived AML cells. Unlike ATP-competitive Syk inhibitors, WC36 was refractory to de novo and acquired drug resistance due to its ability to block not only the Syk kinase activity, but also its noncatalytic scaffolding function that is linked to drug resistance. Collectively, our study shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.

摘要

细胞膜脂质通过直接的脂质-SH2 结构域相互作用来控制含有Src 同源 2 (SH2) 结构域的激酶的细胞活性。在这里，我们报告了新型非脂小分子 SH2 结构域相互作用抑制剂的开发，这些抑制剂可以阻断宿主蛋白的细胞活性。作为一项初步研究，我们评估了脂质-SH2 结构域相互作用抑制剂对脾酪氨酸激酶（Syk）的疗效，Syk 与包括急性髓细胞白血病（AML）在内的造血恶性肿瘤有关。一种优化的抑制剂（WC36）特异性且有效地抑制了 AML 细胞系和患者来源的 AML 细胞中致癌性 Syk 的活性。与 ATP 竞争性 Syk 抑制剂不同，由于其不仅能够阻断 Syk 激酶活性，而且能够阻断与其耐药性相关的非催化支架功能，WC36 对新出现的和获得性耐药性具有抗性。总的来说，我们的研究表明，靶向脂质-蛋白相互作用是开发新型小分子药物的一种有力方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e410/9898191/681895447edd/nihms-1861860-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e410/9898191/168f8cfcbed8/nihms-1861860-f0011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e410/9898191/6bb2f5d7fe05/nihms-1861860-f0002.jpg
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