PF-06869206

Selective inhibitor of SLC34A1

Structure

Information

Protein target names: SLC34A1

Mechanism of action: Selective inhibitor

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 ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

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

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 )