BRD7/BRD9 inhibitor ǀ BI-7273
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
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
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.
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 |
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
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.
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.
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.
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.
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.
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.
An Advanced Tool To Interrogate BRD9
Rezaul M. Karim, Ernst Schönbrunn
J. Med. Chem. 2016, 59, 4459−4461.