Peptidomimetics for Targeting Protein-Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL

Lei Du; Sierrah M Grigsby; Aihong Yao; Yujie Chang; Garrett Johnson; Haiying Sun; Zaneta Nikolovska-Coleska

doi:10.1021/acsmedchemlett.8b00175

Peptidomimetics for Targeting Protein-Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL

ACS Med Chem Lett. 2018 Aug 6;9(9):895-900. doi: 10.1021/acsmedchemlett.8b00175. eCollection 2018 Sep 13.

Authors

Lei Du¹, Sierrah M Grigsby^{2

2}, Aihong Yao¹, Yujie Chang¹, Garrett Johnson², Haiying Sun¹, Zaneta Nikolovska-Coleska^{2

2

2}

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Pathology,Molecular and Cellular Pathology Graduate Program, and Program in Chemical Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.

Abstract

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.