GSK-5959

Antagonist of BRPF1

Structure

Information

Protein target names: BRPF1

Mechanism of action: Antagonist

Recommended in-cell concentration:
between 500 nM and 5 uM
Primary References:

In Vitro Validations

Uniprot ID: P55201
Target Class: Epigenetic
Target SubClass: Bromodomain
Potency: IC50
Potency Value: 0.08 uM
Potency Assay: Time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay, pIC50=7.1.
PDB ID for probe-target interaction (3D structure): 4UYE
Structure-activity relationship: Yes, see PMID 25408830.
Target aliases:
Peregrin, BR140, BRPF1, BRPF1_HUMAN, Protein Br140 ...

In Cell Validations

In Vivo Data

No in Vivo Validations

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SERP ratings and comments


SERP Ratings

In Cell Rating

Comments:

This is a good compound but it has been superseded by GSK6853 chemical probe, which has greatly improved solubility and cell activity.

(last updated: 13 Apr 2017 )

SERP Ratings

In Cell Rating

Comments:

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.

(last updated: 18 Apr 2017 )

SERP Ratings

In Cell Rating

Comments:

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 However, the compound has been superseded by GSK-6853 which is far more potent and well characterised.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

(last updated: 28 Feb 2018 )