CB-5083

Inhibitor of VCP

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 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

Inhibitor

up to 1 uM

Probe Availability:

In Vitro Validations

Uniprot ID: P55072

Target Class: ATPase

Target SubClass: AAA+

Potency: IC50

Potency Value: 11 nM

Potency Assay: ATPase assay

PDB ID for probe-target interaction (3D structure): 6MCK

Structure-activity relationship: yes

Target aliases:

Transitional endoplasmic reticulum ATPase, TERA_HU ...

DOI Reference: 10.1016/j.ccell.2015.10.002

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 DNAPK 500 nM, PDE6 80 nM

Probe Selectivity in Vitro:

off target ATPase inhibition 0/175, Kinase inhibition: 1/173; DNAPK (IC50 = 500 nM; inactive in cells)

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

CB-5083 has been well characterized in terms of its PK profile and cellular activity. In terms of selectivity, it appears to have only been counter-screened in ATPase and kinase panels. The subsequent report by others that it inhibits PDE6, and is indeed only 8-fold selective over PDE6, serves to provide a reminder that any results obtained with CB-5083 should be interpreted with caution as other pharmacology may be at play.

(last updated: 13 Sept 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Choice of concentration is cell-line dependent and is also indication-dependent, most likely. If cytotoxicity is not a desired pharmacological response, using submicromolar concentration may be preferred. Testing at 2 or 3 concentrations would be the most informative approach in such a case. While the listed dose may be suitable, a higher dose - 75 mg/kg QD in mice - is also tolerated and may thus be explored, depending on the indication.

(last updated: 23 Sept 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

This is a well-characterized probe recommended for use in cells and in mice. A wide range of biochemical and cellular measurements support a direct effect on VCP/p97. Notably, resistant alleles have been identified by selection from HCT116 cells. Mouse PK (IV and PO) is available, and numerous studies measuring VCP modulation and downstream cancer phenotypes have been reported using oral administration of 100 mpk CB-5083.

(last updated: 11 Oct 2021 )