A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors.
Nat Chem Biol
; 10(9): 760-767, 2014 Sep.
Article
in En
| MEDLINE
| ID: mdl-25038787
ABSTRACT
Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in kinase active sites have emerged as valuable probes and approved drugs. Many protein classes, however, have functional cysteines, and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative MS to globally map the targets, both specific and nonspecific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent nonkinase proteins that, notably, have conserved active site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental road map to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteome
/
Protein Kinase Inhibitors
Limits:
Humans
Language:
En
Journal:
Nat Chem Biol
Year:
2014
Document type:
Article