PFI-3

Antagonist of SMARCA2, SMARCA4, PBRM1

Structure

Information

Protein target names: SMARCA2, SMARCA4, PBRM1

Mechanism of action: Antagonist

In Vitro Validations

Uniprot ID: P51531
Target Class: Epigenetic
Target SubClass: Bromodomain
Potency: Kd
Potency Value: 81-86 nM
Potency Assay: ITC assay
PDB ID for probe-target interaction (3D structure): 5DKC
Structure-activity relationship: Yes, see J. Med. Chem. paper
Target aliases:
Probable global transcription activator SNF2L2, SN ...

DOI Reference: 10.1021/acs.jmedchem.6b00012

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 first-in-class inhibitor of the BAF bromodomains BRG and BRM. Data is only available for cell-based interogations. In this setting, PFI-3 should enable a range of studies around the cell-based consequences of modulating these important epigenetic targets.

(last updated: 29 Apr 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

PFI-3 represents a well-studied and selective probe for the targets listed, suitable for cellular work.  Care is needed in choosing appropriate cellular concentrations – target engagement is reported at 1uM but other studies report effects at different concentration ranges (Ding et al <0.1uM; Vangamundi et al report 5uM cellular IC50).  The use of the negative control PFI-3oMet is strongly recommended.  The probe developers do not recommend in vivo use; Ding et al report efficacy in a mouse model at 50 mg/kg p.o. so this may be feasible. Obtaining good quality PK data (not presented) is strongly recommended prior to any in vivo work, particularly given the potential for hydrolytic instability in acid - the compound contains a potentially unstable enamide group.  Stability is shown in PBS and cell media for 1 week at neutral pH so there should be no issue for cellular work, however care should be taken with long term storage in solution, or if use at acidic or basic pHs is required which could accelerate decomposition.

(last updated: 29 Apr 2020 )