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.
© 2020 Wiley-VCH GmbH.
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