Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy

Bioorg Med Chem. 2018 Jan 15;26(2):356-365. doi: 10.1016/j.bmc.2017.11.045. Epub 2017 Dec 1.

Abstract

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed.

Keywords: Inhibitors; Leukemia; MLL1; Protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / chemistry
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / genetics
  • Molecular Structure
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
  • Myeloid-Lymphoid Leukemia Protein / chemistry
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / chemistry
  • Protein Binding / drug effects
  • Structure-Activity Relationship

Substances

  • KMT2A protein, human
  • Neoplasm Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase