BPTF inhibitor
BI-7190
BI-7190 was discovered by screening of selected analogues of the BRD9 bromodomain probe BI-95641. The combination of potency, selectivity, and good ADME parameters make it ideal to study the impact of the inhibition mediated by the bromodomain of the epigenetic reader function of BPTF (in vitro and in vivo). BI-4827 is used as negative control in vitro.
More information
BPTF (Bromodomain PHD Finger Transcription Factor) is a core component of the nucleosome remodeling factor (NURF) complex, an essential component of chromatin biology. Knowledge of its function is required to fully understand how the genome is regulated. This protein is a histone-binding component of the NURF complex2. It recognizes acetylated lysines on histone H4, through its bromodomain, as well as di- and tri-methylated lysine 4 on histone H3, through its PHD fingers3-5. The NURF complex catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. The potential pro-tumorigenic role of BPTF has been reported across several indications over the last few years6.
Bromodomain of BPTF with BI-7190, as observed by X-ray
The compound binds with high affinity to BPTF (DiscoveRx KD = 3.5 nM). Cellular target engagement was confirmed by nanoBRET (BPTF EC50 = 58 nM) and a more than 19-fold selectivity window towards the bromodomain family off-targets was observed (e.g., nanoBRET (BRD9) EC50 = 1,100nM).
| PROBE NAME / NEGATIVE CONTROL | BI-7190 | BI-4827 |
| MW [Da, free base]a | 381.5 | 393.4 |
| DiscoveRx (BPTF) (KD) [nM] | 3.5 | > 10,000 |
| ITC (BPTF) (KD) [nM]b | 85 | > 50,000 |
| nanoBRET (BPTF) EC50 [nM] | 58 | > 50,000 |
| nanoBRET (BRD9) EC50 [nM] | 1,100 | > 50,000 |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
b20 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP and 5% (w/v) glycerol
BI-7190 has good solubility in water at neutral pH, high absorptive permeability and a low efflux ratio in the Caco-2 assay, relatively low plasma protein binding and species-dependent in vitro metabolic stability in liver microsomes (low in mouse, moderate to high in rat and human).
| PROBE NAME / NEGATIVE CONTROL | BI-7190 | BI-4827 |
| log D @ pH 11 | 3.3 | 1.7 |
| Solubility @ pH 7 [µg/mL] | > 84 | > 100 |
| Caco-2 permeability AB @ 10 µM [*10-6 cm/s] | 21 | 39 |
| Caco-2 efflux ratio | 1.7 | 1.0 |
| MDCK permeability PappAB @ 10 µM [10-6 cm/s] | 7.2 | 6.4 |
| MDCK efflux ratio | 10 | 7.7 |
| Microsomal stability (human/mouse/rat) [% QH] | 28 / 78 / <23 | <24 / - / <23 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 12 / 91 / 40 | ≤ 6 / 69 / 48 |
| Plasma Protein Binding (human/mouse/rat) [%] | 72 / 67 / 59 | 43 / 33 / 35 |
| hERG (IC50) [µM] | >10 | >10 |
| CYP 3A4 (IC50) [µM] | ≥ 38 | > 50 |
| CYP 2C8 (IC50) [µM] | > 50 | > 50 |
| CYP 2C9 (IC50) [µM] | > 50 | > 50 |
| CYP 2C19 (IC50) [µM] | > 50 | > 50 |
| CYP 2D6 (IC50) [µM] | > 50 | > 50 |
BI-7190 was profiled in mice in an i.v. bolus single dose pharmacokinetic study, resulting in a moderate to high plasma clearance and high volume of distribution. With an oral dose of 30 mg/kg in mice the compound demonstrated efficient intestinal absorption with high plasma exposure and excellent oral bioavailability of 145 % due to non-linear PK.
| BI-7190 | MOUSE |
| Clearance [% QH]a | 64 |
| Vss [L/kg]a | 2.1 |
| Mean residence time after i.v. dose [h]a | 0.6 |
| AUC(0-inf) [nM∙h]b | 33,200 |
| tmax [h]b | 1.0 |
| Cmax [nM]b | 7,900 |
| F [%] | 145 |
a i.v. dose: 5 mg/kg
b p.o. dose: 30 mg/kg
BI-4827 (BPTF KD (BPTF, DiscoveRx) > 10µM) is an inactive analog of BI-7190 and can be used as negative control for in vitro experiments.
BI-4827 which serves as a negative control
No significant hits were observed in Kinase and CEREP panel. BI-7190 shows high selectivity at 10 µM concentration versus a panel of 44 receptors (no inhibition), Kinase panel (38 kinases, no hit at 10 µM).
The negative control BI-4827 shows high selectivity hitting 0/44 targets inhibition with more than 50% @10 µM.
| SELECTIVITY DATA AVAILABLE | BI-7190 | BI-4827 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | Yes | Yes |
| Dundee | No | No |
Download selectivity data:
BI-7190_selectivityData.xlsx
BI-4827_selectivityData.xlsx
The X-ray crystal structure of the BPTF bromodomain in complex with BI-7190 is available (PDB code: 8AG2)1.
NVS-BPTF-17, TP-2388
BI-7190 is a probe to study the impact of BPTF bromodomain inhibition in vitro and in vivo. It binds with high affinity to the bromodomain of BPTF KD (BPTF, DiscoveRx) = 3.5 nM, displays good cellular potency EC50 (BPTF, nanoBRET) = 58 nM, and selectivity to bromodomain family members.
Sensitivity and engineered resistance of myeloid leukemia cells to BRD 9 inhibition
Hohmann A. F., Martin L. J., Minder J. L., Roe J.-S., Shi J., Steurer S., Bader G., McConnell D., Pearson M., Gerstberger T., Gottschamel T., Thompson D., Suzuki Y., Koegl M., Vakoc C. R.
Nat. Chem. Biol. 2016, 12, 672–679.
When you plan a publication, please use the following acknowledgement:
BI-7190 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.