Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma

Oncotarget. 2015 Jun 20;6(17):15122-36. doi: 10.18632/oncotarget.3824.

Abstract

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.

Keywords: B-cell lymphoma; BCR signaling; Btk; irreversible inhibitor; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / chemistry
  • Acrylamides / pharmacology*
  • Adenine / analogs & derivatives
  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Blotting, Western
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism
  • Mice, SCID
  • Microscopy, Confocal
  • Molecular Structure
  • Piperidines
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • RNA Interference
  • Receptors, Antigen, B-Cell / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Acrylamides
  • Antineoplastic Agents
  • Benzamides
  • PLS-123
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Caspases
  • Adenine

Associated data

  • GEO/GSE65816
  • GEO/GSE65817