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Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein–Protein Interactions between DOT1L and MLL-AF9/MLL-ENL
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2022-05-25 , DOI: 10.1021/acs.jmedchem.2c00083
Yinan Yuan 1 , Lei Du 1 , Rongliang Tan 1 , Yifan Yu 1 , Jinxin Jiang 2, 3 , Aihong Yao 1 , Jiajun Luo 1 , Rui Tang 1 , Yibei Xiao 2, 3 , Haiying Sun 1
Affiliation  

On the basis of a previously identified DOT1L peptide mimetic (compound 3), a series of novel peptide mimetics were designed and synthesized. These compounds can potently bind to AF9 and ENL either in cell-free binding assays or in leukemia cells, and selectively inhibit the growth of leukemia cells containing mixed lineage leukemia (MLL) fusion proteins. The most potent compound 12 exhibited comparable anticancer cellular activities to those of EPZ5676, a clinical stage enzymatic inhibitor of DOT1L in several leukemia cell lines containing MLL fusion proteins. Mechanism studies for compound 12 indicated that it did not affect the global methylation of H3K79 catalyzed by DOT1L but could effectively suppress the methylation of H3K79 at MLL fusion proteins targeted genes and inhibit the expressions of these genes. Our studies thus demonstrated that inhibiting the protein–protein interactions between DOT1L and MLL fusion proteins is a potentially effective strategy for the treatment of MLL rearranged leukemias.

中文翻译:

针对 DOT1L 和 MLL-AF9/MLL-ENL 之间蛋白质-蛋白质相互作用的 DOT1L 肽模拟物的设计、合成和生物学评价

在先前鉴定的 DOT1L 肽模拟物(化合物3)的基础上,设计并合成了一系列新型肽模拟物。这些化合物可以在无细胞结合试验或白血病细胞中与 AF9 和 ENL 有效结合,并选择性地抑制含有混合谱系白血病 (MLL) 融合蛋白的白血病细胞的生长。最有效的化合物12表现出与 EPZ5676 相当的抗癌细胞活性,EPZ5676 是几种含有 MLL 融合蛋白的白血病细胞系中 DOT1L 的临床阶段酶抑制剂。化合物12的机理研究表明它不影响 DOT1L 催化的 H3K79 的全局甲基化,但可以有效抑制 MLL 融合蛋白靶向基因处 H3K79 的甲基化并抑制这些基因的表达。因此,我们的研究表明,抑制 DOT1L 和 MLL 融合蛋白之间的蛋白质-蛋白质相互作用是治疗MLL重排白血病的潜在有效策略。
更新日期:2022-05-25
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