Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors.
2018
Abstract The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
27
References
4
Citations
NaN
KQI