GSK778
Probe criteria
| Inhibitor/agonist potency: goal is < 50 nM (IC50, KD) | Surpasses criterion: BET mutant TR-FRET assay:
BRD2 (BD1) pIC50 = 7.1 ± 0.06 (n = 8); (BD2) 5.5 ± 0.26 (n= 10); 40-fold BRD3 (BD1) pIC50 = 7.4 ± 0.09 (n = 8); (BD2) 6.0 ± 0.17 (n = 8); 25-fold BRD4 (BD1) pIC50 = 7.4 ± 0.15 (n = 16); (BD2) 5.2 ± 0.09 (n = 16); 158-fold BRDT (BD1) pIC50 = 6.8 ± 0.09 (n = 8); (BD2) 4.8 ± 0.13 (n = 8); 100-fold BROMOScan (DiscoverX): BRD2(1): Kd = 13 nM; BRD3(1): Kd= 5 nM; BRD4(1): Kd = 5.9 nM; BRDT(1): Kd = 18 nM SPR BRD4 (BD1): pKd = 8.0; BRD4 (BD2) pKd = 5.9 |
| Selectivity within target family: > 30-fold | Surpasses criterion: Excellent selectivity against other BRD containing proteins (Bromoscan) |
| Selectivity outside target family | Selectivity screen (50 targets tested): Closest hits are CHRNA1 (pIC50 = 6) and CYP3A4 (pIC50 = 6)Closest hits in the PDSP scan are DRD3 (Ki =485.92 nM), DRD4 (Ki =856.99 nM), GABAA (Ki =1595.89 nM) and GABAA/BZP (Ki = 1970.29 nM). |
| On target cell activity for cell-based targets: goal is < 1 µM IC50/EC50 | Surpasses criterion: NanoBRET in HEK293 cells: pIC50 = 7.3; Cell proliferation assay with the AML cell line MV-4−11 that has a MLL-AF4 rearrangement (3 days): growth inhibition with pIC50 = 7.0 |