TP-472 A BRD9/7 Probe

This probe is available from Tocris, Cayman Chemical and Sigma.

Its negative control (TP-472N) is available for purchase from Tocris and Sigma.

For any inquiries please contact proberequests@thesgc.org.

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Overview

The bromodomain containing protein 9 (BRD9) has been reported as a component of the switch/sucrose non-fermentable (SWI/SNF) brahma-related gene 1-associated factor (BAF) complex, which plays a key role in chromatin remodelling and transcription control [1] although the precise biological role is unknown. The highly homologous bromodomain containing protein 7 (BRD7) is a component of the SWI/SNF polybromo-associated BAF (PBAF) complex and has been proposed as a tumor suppressor [2].

In a collaborative effort Takeda and the SGC have identified and characterised TP-472 as a BRD9/7 probe. This molecule is of a different chemotype to the BRD9/7 probes previously available, has a structurally similar negative control available (TP-472N), has a good PK profile and is suitable for in vivo applications and is synthetically tractable.

TP-472 has excellent potency (BRD9 K_D 33nM; BRD7 340nM by ITC), selectivity >30 fold over all other bromodomain family members except BRD7 and is cell active (EC₅₀ 320 nM in a BRD9 NanoBRET assay). The negative control TP472N is inactive against other bromodomains (>20uM against BRD9)

Properties

TP-472

TP-472N
(negative control)

Physical and chemical properties for TP-472
Molecular weight	333.1
Molecular formula	C20H19N3O2
IUPAC name	1-(7-(5-(cyclopropylamino-formyl)-2-methyl-phenyl)-1,5-diaza-bicyclo[4.3.0]nona-2,4,6,8-tetraen-9-yl)-ethanone
MollogP	3.102
PSA	46.85
No. of chiral centres	0
No. of rotatable bonds	5
No. of hydrogen bond acceptors	5
No. of hydrogen bond donors	1

Physical and chemical properties for TP-472N (Negative Control)
Molecular weight	306.1
Molecular formula	C19H18N2O2
IUPAC name	1-(7-(2-(cyclopropyl-methoxy)-phenyl)-1,5-diaza-bicyclo[4.3.0]nona-2,4,6,8-tetraen-9-yl)-ethanone
MollogP	3.673
PSA	30.22
No. of chiral centres	0
No. of rotatable bonds	5
No. of hydrogen bond acceptors	4
No. of hydrogen bond donors	0

SMILES:
TP-472: CC(c1cc(c2cc(ccc2C)C(NC2CC2)=O)c2ncccn12)=O
TP-472N: CC(c1cc(c2ccccc2OCC2CC2)c2ncccn12)=O

InChI:
TP-472: InChI=1S/C20H19N3O2/c1-12-4-5-14(20(25)22-15-6-7-15)10-16(12)17-11-18(13(2)24)23-9-3-8-21-19(17)23/h3-5,8-11,15H,6-7H2,1-2H3,(H,22,25)

TP-472N: InChI=1S/C19H18N2O2/c1-13(22)17-11-16(19-20-9-4-10-21(17)19)15-5-2-3-6-18(15)23-12-14-7-8-14/h2-6,9-11,14H,7-8,12H2,1H3

InChIKey:
TP-472: RPBMXJHQYJLPDN-UHFFFAOYSA-N
TP-472N: IDQWBZAMTQTECP-UHFFFAOYSA-N

Selectivity Profile

Selectivity beyond target family

TP-472 and TP-472N were screened in the Eurofins CEREP Diversity Profile to measure binding to a range of Receptors, Ion Channels and enzymes @10 uM. The Inhibition as the mean % of control is shown below, results showing an inhibition or stimulation lower than 50% are considered to represent significant effects. TP-472 showed binding to Adenosine A1 receptor (14%), Benzodiazepine receptor (47%), PDE2A1 (h) (25%), PDE3A (h) (48%) and PDE4D2 (h) (28%). TP-472N showed binding to A1 receptor (35%), A3 receptor (23%), Melatonin receptor MT1 (47%) and Cl- channel (GABA-gated) (20%).

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References

A rationale to target the SWI/SNF complex for cancer therapy, A.F. Hohmann, C.R. Vakoc, Trends Genet, 2014 30, 356–363
BRD7 is a candidate tumour suppressor gene required for p53 function, J. Drost, F. Mantovani, F. Tocco, R. Elkon, A. Comel, H. Holstege, R. Kerkhoven, J. Jonkers, P.M. Voorhoeve, R. Agami, G. Del Sal, Nat Cell Biol, 2010, 58, 380–389