Chemoproteomic Profiling of an Ibrutinib Analogue Reveals its Unexpected Role in DNA Damage Repair

Chembiochem. 2021 Jan 5;22(1):129-133. doi: 10.1002/cbic.202000527. Epub 2020 Oct 20.

Abstract

Ibrutinib is an FDA-approved drug to treat B-lymphoid malignancies, which functions mechanistically as a covalent inhibitor for Bruton's tyrosine kinase (BTK). During the course of screening more potent and selective BTK inhibitors, we discovered that MM2-48, an ibrutinib analogue that contains the alkynyl amide functional group in place of the acrylamide warhead, exhibits a much stronger cytotoxicity. Comparative chemoproteomic profiling of the targets of ibrutinib and MM2-48 revealed that the alkynyl amide warhead exhibits much higher reactivity in proteomes. Unexpectedly, MM2-48 covalently targets a functional cysteine in a BRCA2 and CDKN1A-interacting protein, BCCIP, and significantly inhibits DNA damage repair. Our findings suggest that simultaneous inhibition of BTK activity and DNA damage repair might be a more effective therapeutic strategy for combating B-cell malignancies.

Keywords: BCCIP; Bruton's tyrosine kinase; DNA repair; chemoproteomics; ibrutinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / pharmacology
  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • BRCA2 Protein / antagonists & inhibitors*
  • BRCA2 Protein / chemistry
  • BRCA2 Protein / metabolism
  • Calcium-Binding Proteins / antagonists & inhibitors*
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • DNA Damage
  • Humans
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteomics*

Substances

  • BCCIP protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Piperidines
  • Protein Kinase Inhibitors
  • ibrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • Adenine