Download MendeleyDesign, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors.
Bennett, M.J., Wu, Y., Boloor, A., Matuszkiewicz, J., O'Connell, S.M., Shi, L., Stansfield, R.K., Del Rosario, J.R., Veal, J.M., Hosfield, D.J., Xu, J., Kaldor, S.W., Stafford, J.A., Betancort, J.M.(2018) Bioorg Med Chem Lett 28: 1811-1816
- PubMed: 29657099
- DOI: https://doi.org/10.1016/j.bmcl.2018.04.016
- Primary Citation of Related Structures:
6CKR, 6CKS - PubMed 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.
Organizational Affiliation:
Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, United States.
