GSK620 Chemical Properties

Boiling point:

618.6±55.0 °C(Predicted)

Density 

1.30±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO : 62.5 mg/mL (192.09 mM; Need ultrasonic)

pka

12.43±0.20(Predicted)

form 

Solid

color 

White to off-white

InChI

InChI=1S/C18H19N3O3/c1-19-17(23)15-9-13(16(22)20-14-7-8-14)11-21(18(15)24)10-12-5-3-2-4-6-12/h2-6,9,11,14H,7-8,10H2,1H3,(H,19,23)(H,20,22)

InChIKey

QZZCUOVXHPAQRQ-UHFFFAOYSA-N

SMILES

C1(=O)N(CC2=CC=CC=C2)C=C(C(NC2CC2)=O)C=C1C(NC)=O

GSK620 Usage And Synthesis

Biological Activity

GSK620 is a potent and orally active pan-BD2 inhibitor with excellent broad selectivity, developability and in vivo oral pharmacokinetics. GSK620 is highly selective for the BET-BD2 family of proteins, with >200-fold selectivity over all other bromodomains. GSK620 shows an anti-inflammatory phenotype in human whole blood[1]. GSK620 shows an anti-inflammatory phenotype in human whole blood. Human blood samples are stimulated with LPS, which produces a strong immune response. The monocyte chemattractant protein 1 (MCP-1/CCL2) is measured. This is a chemokine which recruits monocytes, memory T cells, and dendritic cells to sites of inflammation. GSK620 reduces the MCP-1 response in a concentration-dependent manner with (an expected) ～1 log drop off in potency relative to the biochemical BRD4 BD2 potencies observed[1]. Highlighting the utility of GSK620 as an in vivo tool, efficacy is observed in separate models of inflammatory arthritis, psoriasis, and hepatitis[1].

in vitro

GSK620 shows an anti-inflammatory phenotype in human whole blood. Human blood samples are stimulated with LPS, which produces a strong immune response. The monocyte chemattractant protein 1 (MCP-1/CCL2) is measured. This is a chemokine which recruits monocytes, memory T cells, and dendritic cells to sites of inflammation. GSK620 reduces the MCP-1 response in a concentration-dependent manner with (an expected) ～1 log drop off in potency relative to the biochemical BRD4 BD2 potencies observed.

in vivo

Highlighting the utility of GSK620 as an in vivo tool, efficacy is observed in separate models of inflammatory arthritis, psoriasis, and hepatitis.

References

[1]. Seal JT, et al. The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor. J Med Chem. 2020;63(17):9093-9126.

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