Details

Autor(en) / Beteiligte

• Yuan, Yinan
• Du, Lei
• Tan, Rongliang
• Yu, Yifan
• Jiang, Jinxin
• Yao, Aihong
• Luo, Jiajun
• Tang, Rui
• Xiao, Yibei
• Sun, Haiying

Titel

Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein–Protein Interactions between DOT1L and MLL-AF9/MLL-ENL

Ist Teil von

• Journal of medicinal chemistry, 2022-06, Vol.65 (11), p.7770-7785

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.