GSK973
Probe criteria
| Inhibitor/agonist potency: goal is < 50 nM (IC50, KD) | Surpasses criterion: :BET mutant TR-FRET assay:
BRD2 (BD1) pIC50 = 4.4; (BD2) 7.5; 1260-fold BRD3 (BD1) pIC50 = 4.5; (BD2) 7.8; 2000-fold BRD4 (BD1) pIC50 = 4.6 ± 0.1 (n = 19); (BD2) 7.8 ± 0.2 (n = 16); 1600-fold BRDT (BD1) pIC50 = 4.5; (BD2) 7.4; 800-fold BROMOScan (DiscoverX): BRD2 (BD1): pKd =5.3; (BD2) 8.3; 1000-fold BRD3 (BD1): pKd= 5.2; (BD2) 8.5 ; 2000-fold BRD4 (BD1): pKd =5.6; (BD2)8.7; 1260-fold BRDT (BD1): pKd = 5.4; (BD2) 8.3; 800-fold SPR BRD4 (BD1): Kd > 3 µM; BRD4 (BD2) Kd = 34 nM |
| Selectivity within target family: > 30-fold | Surpasses criterion:: BROMOScan (DiscoverX) (34 tested): selective for the BD2 domain of BET proteins; closest hits: TAF1 BD2 (pKd = 6.4), TAF1L BD2 (pKd = 5.7), BRD9 (pKd = 5.7), CECR2 (pKd = 5.5), BAZ2A (pKd = 5.5) and BAZ2B (pKd = 5.1) |
| Selectivity outside target family | Selectivity screen (48 targets tested): clean Chemoproteomics data (3 vectors) showed excellent non BCPs selectivityOff-targets in the PDSP scan are DRD3 Ki = 257.47 nM, DRD4 Ki = 982.65 nM and DRD2 Ki = 964.05 nM |
| On target cell activity for cell-based targets: goal is < 1 µM IC50/EC50 | Surpasses criterion: Lipopolysaccharide (LPS)-stimulated human whole blood assay: MCP-1 (pIC50 =7.3) |
| Control compound (100 times less potent than the probe) | Surpasses criterion: Enantiomer GSK943 BET mutant TR-FRET assay: BRD4 (BD1) pIC50 < 4.3; (BD2) = 5.1, 500-foldClean PDSP scan except for one off-target: GABAA/BZP (Ki = 473.91 nM) |