Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach.
J Med Chem
; 60(24): 10013-10025, 2017 12 28.
Article
in En
| MEDLINE
| ID: mdl-29155568
ABSTRACT
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tankyrases
/
Enzyme Inhibitors
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2017
Document type:
Article
Affiliation country:
Germany
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA