BPTF inhibitor | BI-7190
Highlights
BI-7190 was discovered by screening of selected analogues of the BRD9 bromodomain probe BI-9564.1 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.
Background information
Target 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 complex.2 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 fingers.3-5 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 years.6
Bromodomain of BPTF with BI-7190, as observed by x-ray
In vitro activity
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] | 381.51 | 393.40 |
| DiscoveRx (BPTF) (KD) [nM] | 3.5 | > 10,000 |
| ITC (BPTF) (KD) [nM]a | 85 | > 50,000 |
| nanoBRET (BPTF) EC50 [nM] | 58 | > 50,000 |
| nanoBRET (BRD9) EC50 [nM] | 1,100 | > 50,000 |
a 20 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP and 5% (w/v) glycerol.
In vitro DMPK and CMC parameters
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 |
| clogP | 2.9 | 2.6 |
| Solubility @ pH 6.8 [µg/ml] | > 84 | > 100 |
| CACO permeability Papp, a-b @ 10 µM [*10-6 cm/s] | 21 | 39 |
| CACO efflux ratio | 1.7 | 0.97 |
| MDCK permeability Papp, a-b @ 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) [% bound] | 72 / 67 / 59 | 43 / 33 / 35 |
| hERG [inh. % @ 10 µM] | 15 | 7.9 |
| 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 |
In vivo DMPK parameters
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 |
| Plasma clearance 5 mg/kg i.v. (% QH) | 64 |
| Vss 5 mg/kg i.v. [l/kg] | 2.1 |
| Mean residence time 5 mg/kg i.v. [h] | 0.6 |
| AUC(0-inf) 30 mg/kg p.o. [nM∙h] | 33,200 |
| tmax 30 mg/kg p.o. [h] | 1.0 |
| Cmax 30 mg/kg p.o. [nM] | 7,900 |
| F 5 mg/kg p.o. (%) | 145 |
Negative control
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
Selectivity
No significant hits were observed in Kinase and Cerep panels. 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
Co-crystal structure of the BI probe compound and the target protein
The Xray crystal structure of the BPTF bromodomain in complex with BI-7190 is available (PDB code: 8AG2)1.
Reference molecule(s)
NVS-BPTF-17, TP-2388
Summary
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, and selectivity to bromodomain family members.
Supplementary data
2 D structure formats available
BPTF inhibitor | BI-7190.smiles
Negative Control | BI-4827.png
References
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.
How to cite opnMe?
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://opnme.com.
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