BRD7/BRD9 inhibitor ǀ BI-7273

Target protein: 
BRD7/BRD9
Probe Name: 
BI-7273
MOLECULAR WEIGHT [DA]: 
353.4
In stock: 
2192

Chemical structure

Highlights

BI-7273 was developed in collaboration with the Structural Genomics Consortium (SGC). The potent dual BRD7/BRD9 inhibitor shows 30-fold better potency in the BRD7 AlphaScreen assay compared to our more selective BRD9 inhibitor BI-9564.

BI-7273 binds with high affinity to BRD9 and BRD7 (IC50(BRD9, AlphaScreen) = 19 nM; IC50(BRD7, AlphaScreen) = 117 nM) and is selective versus other BET family members (> 100 µM AlphaScreen). Binding affinity to CECR2 as the only off-target (IC50 (ITC) = 187 nM).

It shows good ADME parameters which make it a suitable probe compound for in vitro and in vivo experiments.1 The negative control BI-6354 is recommended for in vitro experiments.

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Target information

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 inhibition.2

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) cells.3

BRD9 with BI-7273, as observed by X-ray.

Figure 3: BRD9 with BI-7273, as observed by X-ray.1

In vitro Activity

Probe name / Negative control

BI-7273

BI-6354

MW [Da]

353.4

279.3

ITC(BRD9) (KD) [nM]a

15

n.d.

AlphaScreen(BRD9) (IC50) [nM]a

19

27192

AlphaScreen(BRD7) (IC50) [nM]a

117

81896

AlphaScreen(BRD4-BD1) (IC50) [nM]a

>100000

>100000

a for detailed assay conditions see Ref. 1

In vitro DMPK and CMC parameters

Probe name / negative Control

BI-7273

BI-6354

logP

2.0

n.d.

Solubility @ pH 6.8 [µg/ml]

>91

>59

CACO permeability @pH7.4 [*10-6 cm/s]

1.4

n.d.

CACO efflux ratio

26

n.d.

Microsomal stability (human/mouse/rat) [% QH]

<24

56

<23

<24

n.d.

<23

Hepatocyte stability (human/mouse/rat) [% QH]

17

58

7

n.d.

Plasma protein binding (human/mouse/rat) [%]

31

44

33

n.d.

CYP 3A4 (IC50)[µM]

>50

n.d.

CYP 2C8 (IC50)[µM]

>50

n.d.

CYP 2C9 (IC50)[µM]

>50

n.d.

CYP 2C19 (IC50)[µM]

>50

n.d.

CYP 2D6 (IC50)[µM]

>50

n.d.

In vivo DMPK parameters

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]

57a

Mean residence time after iv dose [l/kg]

0.5a

tmax [h]

1.7b

Cmax [nM]

2970b

F [%]

39b

Vss [l/kg]

1.6a

ai.v.5  mg/kg

bp.o. 20 mg/kg

In vivo pharmacology

No in vivo pharmacological studies have been performed with BI-7273.

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
279.3

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. Also see the “In vitro activity” section.

BI-6354 which serves as an in vitro negative control

Figure 4: BI-6354 which serves as an in vitro negative control

Selectivity

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.

BI-7273

Selectivity data available

Cerep®

No

Panlabs®

No

Invitrogen®

Yes

DiscoverX®

Yes

Dundee

No

Download selectivity data: 

Co-crystal structure of the BI probe compound and the target protein

The Xray crystal structure of target in complex with BI-9564 is available (PDB code: 5EU1).1

reference molecules

LP994, I-BRD95, “compound 28”6, BI-95641.7

Summary

BI-7273 is a potent dual BRD7/BRD9 inhibitor with 30 fold better potency in the BRD7 AlphaScreen assay compared to our more selective BRD9 inhibitor BI-9564.

BI-7273 binds with high affinity to BRD9 and BRD7 (IC50(BRD9, AlphaScreen) = 19 nM; IC50(BRD7, AlphaScreen) = 117 nM) and is selective versus other BET family members (> 100 µM AlphaScreen). Binding affinity to CECR2 as the only off-target (IC50 (ITC) = 187 nM).

It shows good ADME parameters which make it a suitable probe compound for in vitro and in vivo experiments to test the biology of BRD7 and BRD9.1,7 The negative control BI-6354 is recommended for in vitro experiments.

Supplementary data

References

  1. Structure-based design of an in vivo active selective BRD9 inhibitor

    Laetitia J Martin, Manfred Koegl, Gerd Bader, Xiao-Ling Cockcroft, Oleg Fedorov, Dennis Fiegen, Thomas Gerstberger, Marco H Hofmann, Anja F Hohmann, Dirk Kessler, Stefan Knapp, Petr Knesl, Stefan Kornigg, Susanne Müller, Herbert Nar, Catherine Rogers, Klaus Rumpel, Otmar Schaaf, Steffen Steurer, Cynthia Tallant, Christopher R. Vakoc, Markus Zeeb, Andreas Zoephel, Mark Pearson, Guido Boehmelt, and Darryl McConnell

    J. Med. Chem. 2016, 59, 4462−4475.

  2. Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance

    Oleg Fedorov, Josefina Castex, Cynthia Tallant, Dafydd R. Owen, Sarah Martin, Matteo Aldeghi, Octovia Monteiro, Panagis Filippakopoulos, Sarah Picaud, John D. Trzupek, Brian S. Gerstenberger, Chas Bountra, Dominica Willmann, Christopher Wells, Martin Philpott, Catherine Rogers, Philip C. Biggin, Paul E. Brennan, Mark E. Bunnage, Roland Schüle, Thomas Günther, Stefan Knapp, Susanne Müller

    Sci. Adv. 2015, 10, e1500723.

  3. Sensitivity and engineered resistance of myeloid leukemia cells to BRD 9 inhibition

    Anja F Hohmann, Laetitia J Martin, Jessica L Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher R Vakoc

    Nat. Chem. Biol. 2016, 12, 672–679.

  4. LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

    Peter G. K. Clark, Lucas C. C. Vieira, Cynthia Tallant, Oleg Fedorov, Dean C. Singleton, Catherine M. Rogers, Octovia P. Monteiro, James M. Bennett, Roberta Baronio, Susanne Müller, Danette L. Daniels, Jacqui Méndez, Prof. Stefan Knapp, Paul E. Brennan, Darren J. Dixon

    Angew. Chem. Int. Ed. Engl. 2015, 54, 6217-21.

  5. Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition

    Natalie H. Theodoulou, Paul Bamborough, Andrew J. Bannister, Isabelle Becher, Rino A. Bit, Ka Hing Che, Chun-wa Chung, Antje Dittmann, Gerard Drewes, David H. Drewry, Laurie Gordon, Paola Grandi, Melanie Leveridge, Matthew Lindon, Anne-Marie Michon, Judit Molnar, Samuel C. Robson, Nicholas C. O. Tomkinson, Tony Kouzarides, Rab K. Prinjha, and Philip G. Humphreys

    J. Med. Chem. 2016, 59, 1425–1439.

  6. Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains

    Duncan A. Hay, Catherine M. Rogers, Oleg Fedorov, Cynthia Tallant, Sarah Martin, Octovia P. Monteiro, Susanne Müller, Stefan Knapp, Christopher J. Schofielda and Paul E. Brennan

    Med. Chem. Commun. 2016, 6, 1381-1386.

  7. An Advanced Tool To Interrogate BRD9

    Rezaul M. Karim, Ernst Schönbrunn

    J. Med. Chem. 2016, 59, 4459−4461.