Prolonged and tunable residence time using reversible covalent kinase inhibitors.
Nat Chem Biol
; 11(7): 525-31, 2015 Jul.
Article
in En
| MEDLINE
| ID: mdl-26006010
ABSTRACT
Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acrylamides
/
Protein-Tyrosine Kinases
/
B-Lymphocytes
/
Cyanoacrylates
/
Protein Kinase Inhibitors
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2015
Document type:
Article
Affiliation country:
Estados Unidos