FHT-2344
| Target | SMARCA2 SMARCA4 |
| Mode of action | Inhibitor |
| Control | FHT-5908 |
| Orthogonal probe | SGC-SMARCA-BRDVIII |
| Recommended cellular usage concentration | ≤ 1 µM |
| In vivo use | yes |
| Donated by | Foghorn Therapeutics |
Probe criteria
| Inhibitor/agonist potency: goal is < 100 nM (IC50, Kd>/sub>) | Surpasses criterion: Measurement of the ATPase catalytic activity using the ADP-Glo™ detection reagent: SMARCA2 (IC50 = 13.8 ± 3.3 nM, n= 8); SMARCA4 (IC50 = 26.1 ± 7.3 nM, n= 8) |
| Selectivity within target family: > 30-fold | Surpasses criterion: Measurement of the ATPase catalytic activity using the ADP-Glo™ detection reagent: CHD4 (IC50 > 200 μM, n= 4)KiNativ platform (ActivX): 200 ATPases tested in A375 cell lysates at 1 and 10 μM: clean |
| Selectivity outside target family | Clean PDSP scanDSF panel with 104 kinases: clean |
| On target cell activity for cell-based targets: goal is < 1 µM IC50/EC50 | Surpasses criterion: Luciferase reporter assay: SMARCA2 transcriptional activity in a SMARCA4-mutant cell line (IC50 = 29.8 ± 13.4 nM; n=7); SMARCA4 transcriptional activity in a SMARCA2-mutant cell line (IC50 = 30.2 ± 8.6 nM; n=6) |
| Control compound (100 times less potent than the probe) | FHT-5908: Measurement of the ATPase catalytic activity using the ADP-Glo™ detection reagent: SMARCA2 (IC50 = 1.88 ± 0.32 μM, n= 5); SMARCA4 (IC50 = 3.99 ± 0.68 μM, n= 5) Luciferase reporter assay: SMARCA2 transcriptional activity in a SMARCA4-mutant cell line (IC50 = 4.35 ± 1.29 μM; n=3); SMARCA4 transcriptional activity in a SMARCA2-mutant cell line (IC50 = 2.37 ± 0.85 μM; n=3)Closest off-targets in the PDSP scan are: SIGMAR1 (Ki = 416.9 nM), HTR2B (Ki = 507.65 nM) |