The therapeutic potential of extra terminal domain inhibitor (iBET) has increasing studies both in oncology and immunoinflammatory. Moreover, iBETs are actively progressing in the clinic for oncology indications. Nevertheless, there have been far fewer reports of selective BET bromodomain inhibitors. Notwithstanding this, the BD2- biased inhibitors maintain a range of immune relevant efficacies in vitro and in vivo. ABBV-744, a highly selective BD2 inhibitor, albeit restricted largely to acute myeloid leukemia and certain prostate cancer cell lines. In this blog, we’d like to introduce a potent and orally active pan-BD2 inhibitor, GSK620.
GSK620 is a potent and orally active pan-BD2 inhibitor with excellent broad selectivity, developability. It also possesses good in vivo oral pharmacokinetics. GSK620 is highly selective for the BET-BD2 family of proteins, with >200-fold selectivity over all other bromodomains. Also, the compound shows an anti-inflammatory phenotype in human whole blood.
Particularly, GSK620 shows an anti-inflammatory phenotype in human whole blood. Human blood samples, stimulated with LPS, produce a strong immune response. Moreover, the monocyte chemoattractant protein 1 (MCP-1/CCL2) is measured. This is a chemokine that recruits monocytes, memory T cells, and dendritic cells to sites of inflammation. In addition, 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 total, the compound has the potential in the study for inflammatory arthritis, psoriasis, and hepatitis
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.