MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo

Cancer Cell. 2012 Dec 11;22(6):812-24. doi: 10.1016/j.ccr.2012.11.003.

Abstract

MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Caspases / metabolism
  • Catalysis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / drug effects
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Protease Inhibitors / pharmacology*
  • Proteolysis
  • Proto-Oncogene Proteins c-rel
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Nuclear Proteins
  • Protease Inhibitors
  • Proto-Oncogene Proteins c-rel
  • REL protein, human
  • Caspases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Associated data

  • GEO/GSE40003