BRD7/BRD9 inhibitor
BI-7273
BI-7273 is a potent dual BRD7/BRD9 inhibitor. This compound binds with high affinity to BRD7 and BRD9 and shows excellent selectivity versus other BET family members. Its overall ADME profile is good, which makes BI-7273 a suitable tool for both in vitro and in vivo experiments. It has good oral bioavailability and has shown moderate to high absorptive permeability and moderate plasma clearances upon i.v. dosing.
BI-7273 was developed in collaboration with the Structural Genomics Consortium (SGC).
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The mammalian switch/sucrose nonfermentable (SWI/SNF) complex is one of four mammalian chromatin remodelling complexes. Recurrent inactivating mutations in certain subunits of this complex have been identified in different cancers. Despite its known roles in tumor suppression, the mammalian SWI/SNF complex has recently received attention as a potential target for therapeutic inhibition2.
The human bromodomain family encompasses 61 domains, found on 46 proteins and BRD9 and BRD7 proteins containing a single acetyl-lysine reader bromodomain are components of the chromatin remodelling SWI/SNF BAF complex. A recent study highlighted a role of another SWI/SNF subunit, BRD9, in leukemia growth. The BRD9 bromodomain (BD) was shown to be required for the proliferation of acute myeloid leukemia (AML) cells3.
BRD9 with BI-7273, as observed by X-ray1.
| PROBE NAME / NEGATIVE CONTROl | BI-7273 | BI-6354 |
| MW [Da, free base]a | 353.4 | 279.3 |
| ITC(BRD9) (KD) [nM]b | 15 | n.a. |
| AlphaScreen(BRD9) (IC50) [nM]b | 19 | 27192 |
| AlphaScreen(BRD7) (IC50) [nM]b | 117 | 81896 |
| AlphaScreen(BRD4-BD1) (IC50) [nM]b | >100000 | >100000 |
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
bFor detailed assay conditions see Ref. 1
| PROBE NAME / NEGATIVE CONTROL | BI-7273 | BI-6354 | ||||
| logP @ pH 11 | 2.5 | 0.6 | ||||
| Solubility @ pH 7 [µg/mL] | >91 | >59 | ||||
| Caco-2 permeability AB @ pH7.4 [*10-6 cm/s] | 1.4 | 63 | ||||
| Caco-2 efflux ratio | 26 | 0.7 | ||||
| Microsomal stability (human/mouse/rat) [% QH] | <24 / 56 / <23 | <24 / n.a. / <23 | ||||
| Hepatocyte stability (human/mouse/rat) [% QH] | 17 / 58 / 7 | n.a. / n.a. / 23 | ||||
| Plasma Protein Binding (human/mouse/rat) [%] | 31 / 44 / 33 | n.a. / n.a. / 62.8 | ||||
| CYP 3A4 (IC50)[µM] | >50 | n.a. | ||||
| CYP 2C8 (IC50)[µM] | >50 | n.a. | ||||
| CYP 2C9 (IC50)[µM] | >50 | n.a. | ||||
| CYP 2C19 (IC50)[µM] | >50 | n.a. | ||||
| CYP 2D6 (IC50)[µM] | >50 | n.a. | ||||
BI-7273 showed moderate to high absorptive permeability and moderate in vivo plasma clearances upon i.v. dosing. BI-7273 displayed good oral bioavailability.
| BI-7273 | MOUSE |
| Clearance [% QH]a | 57 |
| Mean residence time after i.v. dose [L/kg] | 0.5 |
| tmax [h]b | 1.7 |
| Cmax [nM] | 2970 |
| F [%] | 39 |
| Vss [L/kg] | 1.6 |
ai.v. dose: 5 mg/kg
bp.o. dose: 20 mg/kg
No in vivo pharmacological studies have been performed with BI-7273.
BI-6354 is available as an in vitro negative control. It shows only very weak potency on BRD9 and BRD7 and no potency on BRD4.
BI-6354 which serves as an in vitro negative control
BI-7273 was screened on 48 bromodomains and 31 kinases. Beside BRD9 (KD = <1 nM ) and BRD7 (KD = <1 nM) only CECR2 (88 nM) and FALZ (KD = 850 nM) showed a KD < 1 µM in the DiscoverX assay (48 bromodomains). BI-7273 showed a KD of 187 nM in the CECR2 ITC assay, but no cellular effect at 1 µM in FRAP assay. From the 31 kinases only 3 kinases (ACVR1, TGFBR1, ACVR2B) showing an % inhibition of > 43% @10 µM, for which the measured IC50 values were all > 3.5 µM.
| SELECTIVITY DATA AVILABLE | BI-7273 | BI-6354 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | Yes | No |
| Dundee | No | No |
Download selectivity data:
BI-7273_selectivityData_0.xlsx
BI-6354_selectivityData_0.xlsx
The X-ray crystal structure of target in complex with BI-9564 is available (PDB code: 5EU1)1.
LP994, I-BRD95, “compound 28”6, BI-95641,7.
BI-7273 is a dual BRD7/BRD9 inhibitor (IC50,BRD7 = 117 nM, IC50,BRD9 = 19 nM) and shows excellent selectivity versus the BET family.
Structure-based design of an in vivo active selective BRD9 inhibitor
Martin L. J., Koegl M., Bader G., Cockcroft X.-L., Fedorov O., Fiegen D., Gerstberger T., Hofmann M. H., Hohmann A. F., Kessler D., Knapp S., Knesl P., Kornigg S., Müller S., Nar H., Rogers C., Rumpel K., Schaaf O., Steurer S., Tallant C., Vakoc C. R., Zeeb M., Zoephel A,, Pearson M., Boehmelt G., McConnell D.
J. Med. Chem. 2016, 59, 4462−4475.
Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance
Fedorov O., Castex J., Tallant C., Owen D. R., Martin S., Aldeghi M., Monteiro O., Filippakopoulos P., Picaud S., Trzupek J. D., Gerstenberger B. S., Bountra C., Willmann D., Wells C., Philpott M., Rogers C., Biggin P. C., Brennan P. E., Bunnage M. E., Schüle R., Günther T., Knapp S., Müller S.
Sci. Adv. 2015, 10, e1500723.
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.
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
Clark P. G. K., Vieira L. C. C., Tallant C., Fedorov O., Singleton D. C., Rogers C. M., Monteiro O. P., Bennett J. M., Baronio R., Müller S., Daniels D. L., Méndez J., Prof. Knapp S., Brennan P. E., Dixon D. J.
Angew. Chem. Int. Ed. Engl. 2015, 54, 6217-21.
Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition
Theodoulou N. H., Bamborough P., Bannister A. J., Becher I., Bit R. A., Che K. H., Chung C. W., Dittmann A., Drewes G., Drewry D. H., Gordon L., Grandi P., Leveridge M., Lindon M., Michon A.-M., Molnar J., Robson S. C., Tomkinson N. C. O., Kouzarides T., Prinjha R. K., Humphreys P. G.
J. Med. Chem. 2016, 59, 1425–1439.
Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains
Hay D. A., Rogers C. M., Fedorov O., Tallant C., Martin S., Monteiro O. P., Müller S., Knapp S., Schofielda C. J., Brennan P. E.
Med. Chem. Commun. 2016, 6, 1381-1386.
When you plan a publication, please use the following acknowledgement:
BI-7273 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.