dBRD9 Chemical Properties

Boiling point:

1014.2±65.0 °C(Predicted)

Density 

1.357±0.06 g/cm3(Predicted)

pka

10.74±0.40(Predicted)

form 

Solid

color 

Light yellow to yellow

InChIKey

AIOCFZJGGGEWDK-UHFFFAOYSA-N

SMILES

O=C1N(C2CCC(=O)NC2=O)C(=O)C2=CC=CC(NCCOCCOCCNC(=O)CN(C)CC3C(=CC(C4=CN(C)C(=O)C5=CN=CC=C45)=CC=3OC)OC)=C12

dBRD9 Usage And Synthesis

Description

dBRD9 is a potent and selective Degrader (PROTAC?) of BRD9 (IC50 = 56.6 nM in MOLM-13 cells). dBRD9 is composed of the BRD9 inhibitor BI 7273 conjugated to the cereblon E3 ligase ligand pomalidomide. Does not degrade BRD4 or BRD7 at concentrations up to 5 μM. Displays antiproliferative effects in human AML cell lines.

Uses

dBRD9,a PROTAC, can selective degrades BRD9. dBRD9 improves the bromine domain binding profile and reduces the binding activity of the whole BET family[1].

Biological Activity

dBRD9 is a PEG-linked pomalidomide conjugate and was found to prompt rapid BRD9 degradation over a broad range of concentrations. Besides, also shows an improved bromodomain engagement profile, with reduced binding activity across the BET family. Meanwhile, dBRD9 (0.5, 5, 50, 500, 5000 nM; 4 h) decreases the expression of BRD9 protein in MOLM-13 cells in a dose-dependent manner. However, it shows no significant effect on the expression of BRD4 and BRD7 proteins. Moreover, dBRD9 (100 nM; 2 h) shows selectivity for BRD9 degradation with a 5.5 median fold lower abundance in dBRD9 treated samples in MOLM-13 cells. However, the levels of other proteins were remarkably static between treatments, with 99% of proteins differing less than 0.30 fold. In addition, dBRD9 (0-100; 7 days) shows a potent anti-proliferative effect in EOL-1 and MOML-13 cells in a dose-dependent manner. All in all, dBRD9 is a PROTAC and can selectively degrade BRD9.

IC 50

BRD9

References

[1] Remillard D, et al. Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands. Angew Chem Int Ed Engl. 2017 May 15;56(21):5738-5743. DOI:10.1002/anie.201611281