PF-06869206

PF-06869206 : Inhibitor of SLC34A1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe PF-06869206 is in the process of SERP review.

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Information

SLC34A1

Inhibitor

up to 10 uM

Probe Availability:

In Vitro Validations

Uniprot ID: Q06495

Target Class: Other

Target SubClass: SLC Family

Potency: IC50

Potency Value: 350 nM

Potency Assay: Displacement of tritiated compound 6b from NaPi2a Membranes

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

Structure-activity relationship: yes

Target aliases:

Sodium-dependent phosphate transport protein 2A, S ...

DOI Reference: 10.1021/acsmedchemlett.8b00013

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency in cells, off target : IC50

Probe Selectivity in Cell:

NaPi2b, NaPi2c, PiT-1, PiT2, Parental HEK IC50 >25 uM

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

The probe is a micromolar inhibitor of the NaPi2a sodium-phosphate cotransporter in cells (direct target engagement is not confirmed). There are limited data describing the selectivity of the probe. In vivo PKPD data in wild-type and knock-out mouse suggest the probe is suitable for assessing NaPi2a pharmacology when used orally at high doses (>30 mg/kg), but other off-target effects are unknown.

(last updated: 22 Feb 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

There are no biochemical assays reported for this target so all inhibition data have been generated in cellular assays. The IC50 value of 0.38 uM was determined in HEK293 cells stably expressing NaPi2a and measuring cellular transport of radiolabelled phosphate. The selectivity against related transporters and activity against the rat (IC50 = 0.40 uM) and mouse (IC50 = 0.54 uM) transporter were determined in similar HEK29-based cellular assays. A Ki value of 0.75 uM was determined from displacement of tritiated compound 6b from membrane of NaPi2a expressing cells. PF-06869206 also showed dose-dependent inhibition of phosphate transport in human proximal tubule cells (32% inhibition @ 1 uM), primary rat PRT cells (46% inhibition @ 30 uM) and opossum kidney cells (IC50 ~1.4 uM).

In vivo IC50 for urinary phosphate excretion was determined to be 21-23 mg/kg in wild type mice with acute dosing. Chronic dosing in nephrectomised rats @ 300 mg/kg daily for 8 weeks was well tolerated and led to maximal response in urinary phosphate excretion and serum phosphate level, both indicative of NaPi2a inhibition.

(last updated: 26 Feb 2021 )