1 research outputs found
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300
The single bromodomain of the closely
related transcriptional regulators
CBP/EP300 is a target of much recent interest in cancer and immune
system regulation. A co-crystal structure of a ligand-efficient screening
hit and the CBP bromodomain guided initial design targeting the LPF
shelf, ZA loop, and acetylated lysine binding regions. Structure–activity
relationship studies allowed us to identify a more potent analogue.
Optimization of permeability and microsomal stability and subsequent
improvement of mouse hepatocyte stability afforded <b>59</b> (GNE-272, TR-FRET IC<sub>50</sub> = 0.02 μM, BRET IC<sub>50</sub> = 0.41 μM, BRD4(1) IC<sub>50</sub> = 13 μM) that retained
the best balance of cell potency, selectivity, and in vivo PK. Compound <b>59</b> showed a marked antiproliferative effect in hematologic
cancer cell lines and modulates <i>MYC</i> expression in
vivo that corresponds with antitumor activity in an AML tumor model