当前位置: X-MOL 学术Nat. Chem. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting lipid–protein interaction to treat Syk-mediated acute myeloid leukemia
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2022-10-13 , DOI: 10.1038/s41589-022-01150-z
Indira Singaram 1 , Ashutosh Sharma 1 , Shashank Pant 2, 3 , Muyun Lihan 2 , Mi-Jeong Park 4 , Melissa Pergande 1 , Pawanthi Buwaneka 1 , Yusi Hu 1, 5 , Nadim Mahmud 6 , You-Me Kim 7 , Stephanie Cologna 1 , Vladimir Gevorgyan 8 , Irum Khan 6 , Emad Tajkhorshid 2 , Wonhwa Cho 1
Affiliation  

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.



中文翻译:

靶向脂蛋白相互作用治疗 Syk 介导的急性髓性白血病

膜脂通过直接的脂质-SH2 结构域相互作用控制含有 Src 同源 2 (SH2) 结构域的激酶的细胞活性。在这里,我们报告了脂质-SH2 结构域相互作用的新型非脂质小分子抑制剂的开发,这些抑制剂可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脏酪氨酸激酶 (Syk) 的疗效,它与造血系统恶性肿瘤有关,包括急性髓系白血病 (AML)。优化的抑制剂 (WC36) 在 AML 细胞系和患者来源的 AML 细胞中特异性且有效地抑制 Syk 的致癌活性。与 ATP 竞争性 Syk 抑制剂不同,WC36 很难从头开始并获得耐药性,因为它不仅能够阻断 Syk 激酶活性,以及与耐药性相关的非催化支架功能。总的来说,我们的研究表明,靶向脂质-蛋白质相互作用是开发新的小分子药物的有效方法。

更新日期:2022-10-14
down
wechat
bug