A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia

EMBO Mol Med. 2013 Mar;5(3):353-65. doi: 10.1002/emmm.201201760. Epub 2013 Jan 22.

Abstract

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34(+) progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homologous Recombination / drug effects
  • Humans
  • Imatinib Mesylate
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Docking Simulation
  • Mutation
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Piperazines / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / metabolism
  • Proteasome Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Pyrimidines / pharmacology*
  • RNA Interference
  • Rad51 Recombinase / antagonists & inhibitors*
  • Rad51 Recombinase / chemistry
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Tetrahydroisoquinolines / metabolism
  • Tetrahydroisoquinolines / pharmacology*
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects

Substances

  • (R)-1-(1H-indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroisoquinoline
  • Antineoplastic Agents
  • Benzamides
  • Indoles
  • Piperazines
  • Proteasome Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tetrahydroisoquinolines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • RAD51 protein, human
  • Rad51 Recombinase
  • Rad51 protein, mouse
  • Proteasome Endopeptidase Complex