VH298

Protein-protein interaction inhibitor of VHL

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

Protein-protein interaction inhibitor

10-100 μM

Probe Availability:

In Vitro Validations

Uniprot ID: P40337

Target Class: Other post-translational modification

Target SubClass: E3 ubiquitin ligase

Potency: Kd

Potency Value: 90 nM

Potency Assay: Isothermal calorimetry assays, VH298 bounding VBC. SPR, VH298 had a Kon = 6.47 X 10^5/M*sec and a Koff = 0.065/sec.

PDB ID for probe-target interaction (3D structure): 5LLI

Structure-activity relationship: See Galdeano et al., J. Med. Chem. 2014 (doi: 10.1021/jm5011258)

Target aliases:

von Hippel-Lindau disease tumor suppressor, VHL, V ...

DOI Reference: 10.1038/ncomms13312

Uniprot ID: P40337

Target Class: Other post-translational modification

Target SubClass: E3 ubiquitin ligase

Potency: Kd

Potency Value: 80 nM

Potency Assay: Fluorescence polarization assays using a HIF-1alpha peptide, VH298 bounding VBC

PDB ID for probe-target interaction (3D structure): --

Target aliases:

von Hippel-Lindau disease tumor suppressor, VHL, V ...

DOI Reference: 10.1038/ncomms13312

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

In Dundee MRC-PPU Express Screen of 50 kinases, VH298 did not substantially inhibit any kinases at 50 uM. In CEREP ExpressProfile assay of 50 GPCRs and ion channels, VH298 did not bind any targets at 50 uM.

Probe Selectivity in Cell:

In chemoproteomic MS assays using an immobilized, linkable analogue of VH298, RBX1, CUL2, VHL, and TCEB2 were the only proteins that were reproducibly detected in a dose-dependent competition experiment.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

Aqueous solubility data should be provided for this probe.

(last updated: 29 Dec 2016 )

SERP Ratings

In Cell Rating

SERP Comments:

A useful probe that blocks VHL:HIF-a interaction.

(last updated: 3 Jan 2017 )

SERP Comments:

The probe is soluble in DMSO at concentrations >100 mM.

(last updated: 1 May 2017 )

SERP Comments:

Author note: Regarding "Aqueous solubility data should be provided for this probe."

We have now measured the solubility of this probe. VH298 was soluble at 250 uM in water (unbuffered solution) in the presence of 2.5% v/v DMSO.

(last updated: 1 Jun 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

A selective probe that inhibits the VHL-HIFa interaction. There is a large difference between FP, ITC, and SPR-determined affinity and cell-based activity (recommended for use at 10-100 uM). I recommend performing isothermal dose response CETSA to assess affinity for VHL in cells.

(last updated: 12 Jun 2017 )