GSK-5959

This is a good compound but it has been superseded by GSK6853 chemical probe, which has greatly improved solubility and cell activity.

This benzimidazolone probe inhibits BRPF1 (bromodomain and PHD finger-containing domain 1). Biochemical data using a TR-FRET format shows an IC₅₀ of 80 nM against BRPF1 with 100X less potency against BRPF2 and high selectivity against BRPF3. Activity was measured against over 35 bromodomains, which also showed high selectivity. Further validation of binding to BRPF1 includes NMR and a X-ray co-crystal structure; however, the Kd was not mentioned. Cell-based data confirms cell penetration in a target-engagement assay (NanoBRET) with an IC₅₀ ~ 1 uM. Further cell-based functional data would enhance confidence for the usefulness this probe in cell-based studies.

GSK-5959 is a reasonably potent (TR-FRET pIC50 7.1), selective (>100 fold over other BRDs) and cell permeable/cell active (NanoBRET pIC50 6.0). However, the compound has been superseded by GSK-6853 which is far more potent and well characterised. GSK-5959 poses as a useful in vitro tool molecule but as a broader profiling of its off-target activity has not been reported, users should approach screening at high cellular concentrations with caution. The cell target engagement of the compound has been measured using a NanoBRET displacement assay with a NanoLuc tagged Bromodomain-only construct of BRPF1- no mention is made why other constructs were not used. The benzimidazolones are a privileged scaffold for BRPF Brd inhibition (OF-1, PFI-4, BAY-299, GSK-5959, GSK-6853), whilst use of these molecules in concert to investigate BRPF biology is encouraged, ideally other structurally distinct chemotypes should be used. GSK-6853 superseding probe: 10.1021/acsmedchemlett.6b00092