PF-06869206

Protein target name:

SLC34A1

Mechanism of action:

Selective inhibitor

Recommended Concentration for use in cells:

up to 10 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Subclass:

SLC Family

HUGO ID:

HGNC:11019

Entrez gene ID:

6569

UNIPROT ID:

Q06495

Target alias:

FRTS2, HCINF2, NAPI-3, NPHLOP1, NPT2, NPTIIa, SLC11, SLC17A2

Probe Details

Chemical Probes Portal ID:

CPP2054

Probe alias:

cpd 6f, NaPi2a inhibitor

PubChem CID:

134159047

ChEMBL ID:

CHEMBL4175607

SMILES string:

ClC1=C(C)NC2=C(N3C[C@@H](CO)OCC3)C(C#N)=C(C(F)(F)F)N=C21

InChi Key:

ATFQBBCQZKVZJN-QMMMGPOBSA-N

Physico-chemical properties

Solubility - concentration:

46 uM

NMR:

1H NMR (400MHz, DMSO-d6) δ 11.78 (br. s, 1H), 4.85 (t, J=5.3 Hz, 1H), 4.00 (d, J=10.9 Hz, 1H), 3.82–3.40 (m, 7H), 3.40–3.28 (m, 1H), 2.56–2.39 (s, 3H).

13C NMR (101MHz, DMSO-d6) δ 147.7, 143.2 (q, J=33.0 Hz, 1C), 142.4, 141.1, 119.5, 121.3 (q, J=275.3 Hz, 1C), 115.7, 104.1, 89.8, 76.5, 66.1, 61.9, 52.9, 50.5, 11.6.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

350 nM

Potency assay:

Displacement of tritiated compound 6b from NaPi2a Membranes

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Probe Selectivity in Vitro:

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

In cell validation

On target activity in cells

Potency in cells:

IC50

1.4 uM

Potency assay (cells):

Dose dependent inhibition of NaPi2a in OK cells

In vivo validation

Organism:

Wistar–Han ratC57BL6 mouse

Dose:

1 mg/Kg IV5 mg/Kg PO50 mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

4.8 h (R)0.75 h (M)

Systemic clearance:

15(R), 22(M) mL/min/Kg

Fraction of probe bound to plasma protein:

87, 140 % (5, 50 mg/Kg PO, R)27, 240 % (5, 50 mg/Kg PO, M)

Cmax:

720, 6000 ng/mL (5, 50 mg/Kg PO, R)540, 11000 ng/mL (5, 50 mg/Kg PO, M)

Tmax:

0.75, 1.0 h (5, 50 mg/Kg PO, R)0.38, 1.5 h (5, 50 mg/Kg PO, M)

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.8b00013 10.1152/ajprenal.00146.2020

Reference (PMID):

29795756 32744087

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB 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.

Feb 22 2021 - 4:52pm

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.

Feb 26 2021 - 4:29pm

PF-06869206

Probe Availability

Probe Information

Target Details

FRTS2, HCINF2, NAPI-3, NPHLOP1, NPT2, NPTIIa, SLC11, SLC17A2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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PF-06869206

Probe Availability

Probe Information

Target Details

FRTS2, HCINF2, NAPI-3, NPHLOP1, NPT2, NPTIIa, SLC11, SLC17A2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?