3.2M
focused library screened
94
hit candidates
selected
17
compounds with high
affinity to BRD4
3
potent hits
identified
01/ Background
- The target is Human Bromodomain-containing protein 4 (BRD4) — transcription factor with an important role in cancer development.
- BRD4 is a member of a family of at least four proteins sharing the same structural motif.
02/ Methodology
- 3.2M compounds were prefiltered from 11M stock library based on 16 psychem/druglike filters.
- QuorumMap optimization parameters defined by project input.
- Optimization loop included docking against target and off-targets with ArtiDock and ADME-Tox prediction with ADMTETIQ
- After 100 cycle runs, optimzation reached a plateau.
- 94 compounds were selected for in vitro validation.
- Differential scanning fluorimetry assay performed.
03/ Results
- 17 compounds demonstrated a significant binding effect.
- 8 of them belong to known classes of BRD4 inhibitors.
- 9 hits are entirely new to BRD4, representing 8 chemical classes.
*Difference between BRD4-control and
BRD4-ligand complex melting temperatures
BRD4-ligand complex melting temperatures
04/ Best Compound
- Previously unknown class of BRD4 inhibitors.
- Has shown the highest potency in experiments (IC50 = 470 nM).
