BI-2545

Protein target name:

ENPP2

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Phosphodiesterase

Subclass:

Phosphodiesterase

HUGO ID:

HGNC:3357

Entrez gene ID:

5168

UNIPROT ID:

Q13822

Target alias:

ATX; NPP2; ATX-X; PDNP2; LysoPLD; AUTOTAXIN; PD-IALPHA

Probe Details

Chemical Probes Portal ID:

CPP1852

Probe alias:

BI2545, Compound 19

PubChem CID:

131953432

ChEMBL ID:

CHEMBL4165749

SMILES string:

O=C(NC[C@H]1[C@@H]2CN(C(=O)OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]12)c1ccc2[nH]nnc2c1

InChi Key:

ZDOBSAPHUUUOHX-OSYLJGHBSA-N

Control compound:

BI-3017

Orthogonal probe:

PF-8380

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 - 8.73 (m, 1 H), 8.46 (br s, 1 H), 8.05 (s, 3 H), 7.94 (s, 2 H), 5.22 (d, J=4.69 Hz, 2 H), 3.59 (d, J=10.52 Hz, 1 H), 3.52 (d, J=10.65 Hz, 1 H), 3.45 (dd, J=10.46, 3.87 Hz, 1 H), 3.37 (dd, J=10.65, 3.93 Hz, 1 H), 3.26 (t, J=6.21 Hz, 2 H), 1.55 - 1.64 (m, 2 H), 0.86 (tt, J=6.75, 3.33 Hz, 1 H). Note: The nitrogen bonded triazole proton could not be observed due to fast exchange.

13C NMR (100 MHz, DMSO-d6) δ ppm 165.8, 153.8, 140.6, 131.5, 130.7, 130.3 (q, J=32.8 Hz, 2 C), 128.1 (s, 2 C), 123.2 (q, J=272.8 Hz, 2 C), 121.4, 115.2, 113.8, 64.4, 48.4, 47.8, 40.8, 22.3, 21.5, 20.6.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

2.2 nM (human); 3.4 nM (rat)

Potency assay:

LPA measurement

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

5OHI 5OLB

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

IC50

29 nM (human) 96 nM (rat)

Potency assay (cells):

Whole blood assay

Off target activity in cells

Probe Selectivity in Cell:

At 10 µM (CEREP): 4/48 off targets >50% (5-HT2A, Ca2+ channel, Na+ channel, norepinephrine transporter)

In vivo validation

Organism:

Rat

Dose:

10 mg/Kg PO1 mg/Kg IV

Route of delivery:

OralIntravenous

Plasma half life:

3.4 h

Systemic clearance:

7 ml/(min*Kg)

Cmax:

149 nM

Tmax:

1.7 h

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.7b00312

Reference (PMID):

29259743

External Resources

Available data:

SGC additional analysis

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

Part of the Donated Chemical Probes initiative from SGC.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

BI-2545 represents a suitable chemical probe for ENPP2. While of a similar chemical class to PF-8380, BI-2545 is more potent in whole blood experiments and achieved high in vivo potency when administered orally in rat. Additionally, a structurally negative control is provided with BI-3017 to aid in experiments

Jun 28 2020 - 8:56am

In the original article, the compound is dissolved in 0.5% Natrosol For p.o. admistration. The compound can also be administered i.v. by dissolving in 7% HP-β-CD.

Jun 28 2020 - 8:58am

The benzotriazole BI-2545 compound is a potent inhibitor of human Autotaxin (ATX) both in cells (IC50 of 29 nM) and in vivo (IC50 of 96 nM in rodents).

ATX is an enzyme that controls levels of lysophosphatidic acid (LPA) by converting

lysophosphatidylcholine (LPC) into LPA. LPA is involved in cell signalling, mediating a wide range of biological effects in many tissue type, and it is associated to disease pathology characterised by abnormal cell migration. In vivo studies have shown that a single oral dose of BI-2545 at 10 mg/kg a LPA reduction of up to 90% in rats.

The crystal structure of ATX in complex with BI-2545 is available (PDB ID: 5OHI, 1.66 Å resolution). This compound belongs to the Type I inhibitors that occupy the orthosteric site, mimicking the LPC substrate mode of binding.

The compound has been developed for the potential treatment of idiopathic pulmonary fibrosis (IPF), but inhibition of ATX has also been investigated as promising target for treating chronic inflammatory diseases that underlie several other medical conditions, such as cancer, cardiovascular diseases, and rheumatoid arthritis.

This compound is a valuable chemical probe, and it has the advantage that there is another molecule from the same family of compounds that can be used as inactive control (compound BI-3017, also freely available).

Jun 28 2020 - 9:00am

BI-2545

Probe Availability

Probe Information

Target Details

ATX; NPP2; ATX-X; PDNP2; LysoPLD; AUTOTAXIN; PD-IALPHA

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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BI-2545

Probe Availability

Probe Information

Target Details

ATX; NPP2; ATX-X; PDNP2; LysoPLD; AUTOTAXIN; PD-IALPHA

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?