Peptidomimetics for Targeting Protein-Protein Interactions between DOT1 L and MLL Oncofusion Proteins AF9 and ENL

被引：21

作者：

Du, Lei ^{[1
]}

Grigsby, Sierrah M. ^{[2
,3
]}

Yao, Aihong ^{[1
]}

Chang, Yujie ^{[1
]}

Johnson, Garrett ^{[4
]}

Sun, Haiying ^{[1
]}

Nikoloyska-Coleska, Zaneta ^{[2
,3
,4
]}

机构：

[1] China Pharmaceut Univ, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Jiangsu, Peoples R China

[2] Univ Michigan, Med Sch, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Med Sch, Mol & Cellular Pathol Grad Program, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Med Sch, Program Chem Biol, Ann Arbor, MI 48109 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 09期

基金：

美国国家科学基金会;

关键词：

MLL fusion proteins; DOT1L; peptidomimetics; protein-protein interactions; MIXED-LINEAGE LEUKEMIA; H3K79; METHYLATION; ELONGATION COMPLEX; FUSION-PROTEINS; LEUKEMOGENESIS; RECRUITMENT; TRANSCRIPTION; CELLS;

D O I：

10.1021/acsmedchemlett.8b00175

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

MLL-fusion proteins, AF9 and ENL, play an essential role in the recruitment of DOT1L and the H3K79 hypermethylation of MLL target genes, which is pivotal for leukemogenesis. Blocking these interactions may represent a novel therapeutic approach for MLL-rearranged leukemia. Based on the 7 mer DOT1L peptide, a class of peptidomimetics was designed. Compound 21 with modified middle residues, achieved significantly improved binding affinities to AF9 and ENL, with K-D values of 15 nM and 57 nM, respectively. Importantly, 21 recognizes and binds to the cellular AF9 protein and effectively inhibits the AF9-DOT1L interactions in cells. Modifications of the N- and C-termini of 21 resulted in 28 with 2-fold improved binding affinity to AF9 and much decreased peptidic characteristics. Our study provides a proof-of-concept for development of nonpeptidic compounds to inhibit DOT1L activity by targeting its recruitment and the interactions between DOT1L and MLL-oncofusion proteins AF9 and ENL.

引用

页码：895 / 900

页数：11

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