CCT251236

CCT251236 : pirin ligand of PIR

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

pirin ligand

10-100 nM

Probe Availability:

In Vitro Validations

Uniprot ID: O00625

Target Class: Other

Target SubClass: Cupin

Potency: KD

Potency Value: 44 nM

Potency Assay: Surface Plasmon Resonance

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

Structure-activity relationship: SAR for 8 analogues are available as affinities measured by SPR. The SAR is consistent with the binding mode described in by the crystal structure.

Target aliases:

Pirin, PIR, PIR_HUMAN, Probable quercetinase, Prob ...

DOI Reference: 10.1021/acs.jmedchem.6b01055

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): There are no known proteins that are family members with pirin. Pirin is a member of the cupin superfamily of proteins which all possess a similar structural feature, the core beta-barrel but retain no sequence or binding site homology and no common endogenous ligand.

Probe Selectivity in Vitro:

Kinomescan assay of 442 kinases for the chemical probes parent compound yielded 4 kinases that were inhibited >90% at 1 uM (KIT, PDGFRA, PFGFRB, BRAF). IC50s for KIT, PDGFRA and PDGFRB were >10,000 nM. IC50 for BRAF=420 nM; however, assessment of chemically unrelated BRAF inhibitors yielded no activity in the phenotypic screen, indicating that CCT251236 activity in the screen was not attributable to BRAF. Cerep Diversity Screen of 98 molecular targets gave 4 hits which displayed >80% inhibition at 10 uM, adenosine A2A and A3 receptors, histamine H2 and H3 receptors, muscarinic receptor and acetylcholine esterase.

Potency assay, off target (cells): GSK3beta and PDE6D were also identified in the proteomic assays but ruled out as targets in follow-up experiments.

Probe Selectivity in Cell:

Not available

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

This is a useful probe for Pirin - useful to study Pirin function both in cells and in vivo. There is a correlation of molecule binding to Pirin and cellular activity. Active and inactive versions of the molecule have been reported, and the inactive version should be used as a control.

(last updated: 26 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

CCT251236 has been thoroughly investigated and characterized as a cellular probe for Pirin (target) and HSF (pathway) and is supported by a robust and transparent set of data. My only concern is for possible in vivo use where there is an apparent non-linear pharcacokinetic response in mouse (20 mg/kg, oral dose gave a 3-fold lower AUC than a 5 mg/kg dose, albeit in a different mouse strain). I suggest users run a pilot PK study in their strain of interest to ensure the required exposures can be achieved with their dose.

(last updated: 12 Jun 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

While CCT251236 clearly shows potent binding (SPR) to human pirin, displays potent inhibition of Hsp72 induction in a cell-based assay (ELISA), and shows activity in an SK-OV-3 mouse xenograft study, this chemical probe may well be active against other targets, since the anti-proliferative activity against a panel of cancer cell lines is often more potent than the potency measured by the assays outlined above. The enduser should thus use caution when interpreting cell-based or in vivo results obtained using CCT251236.

(last updated: 12 Mar 2021 )