PZ-2891

Protein target name:

PANK1, PANK2, PANK3

Mechanism of action:

Allosteric Activator, Orthosteric Inhibitor

Recommended Concentration for use in cells:

up to 10 uM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Pantothenate kinase

HUGO ID:

HGNC:8598 HGNC:15894 HGNC:19365

Entrez gene ID:

53354 80025 79646

UNIPROT ID:

Q8TE04 Q9BZ23 Q9H999

Target alias:

PANK, C20orf48, HARP, HSS, NBIA1, PKAN

Probe Details

Chemical Probes Portal ID:

CPP2334

Probe alias:

7DQ

PubChem CID:

132260806

SMILES string:

N#CC1=NN=C(N2CCN(C(CC3=CC=C(C(C)C)C=C3)=O)CC2)C=C1

InChi Key:

LGWDVWIZDPGCFG-UHFFFAOYSA-N

Control compound:

PZ-3067

Physico-chemical properties

Solubility - concentration:

23 uM

NMR:

1H NMR (400 MHz, Chloroform-d) δ 8.46 (dd, J = 2.4, 0.8 Hz, 1 H), 7.69 (dd, J = 9.0, 2.3 Hz, 1 H), 7.38–7.32 (m, 2 H), 7.30 (d, J = 2.1 Hz, 2 H), 6.63 (dd, J = 9.0, 0.9 Hz, 1 H), 6.31 (s, 1 H), 3.83 (m, 4 H), 3.74–3.65 (m, 4 H), 1.32 (s, 9 H);

13C NMR (101 MHz, CDCl3) δ 155.21, 152.77, 146.72, 140.23, 135.95, 125.99, 120.16, 105.84, 97.27, 43.93, 43.28, 34.45, 31.54

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50,KD

PANK1 40.2 ± 4.4 nM, PANK2 0.7 ± 0.08 nM, PANK3 1.3 ± 0.2 nM, 0.203 nM PANK3 (KD)

Potency assay:

SPR, radiochemical kinase assay, Thermal stabilisation

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

6B3V

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

PZ-2891 did not have significant inhibitory activity in a screen of 468 mammalian kinases.

Outside Target Family: A screen on 72 cellular proteins known to cause off-target effects in drug discovery highlighted that PZ-2891 selectively target PANK in cells and indicated the absence of off-target pharmacological interactions.

In cell validation

On target activity in cells

Potency in cells:

K 0.5

8.7 ± 2.6 uM

Potency assay (cells):

TLC with Radio-labelled Panthotenate, CETSA Cell Lines used: C3A, HEK293T exogenously expressing PANK3

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

no evidence of cytotoxicity

In vivo validation

Organism:

C57Bl6/J mice

Dose:

2 (IV), 10 (PO) mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

0.28 h (IV)

Systemic clearance:

54.51 (IV) ml/min/Kg

Cmax:

2808.32 ng/ml (IV), 1886.47 ng/ml (PO)

Tmax:

0.25 h (PO)

Vss:

0.94 L/Kg (IV)

AUC:

611.48 (hr*ng/mL) IV, 1024.03 (hr*ng/mL) PO

Bioavailability:

46 %

Primary Reference

Reference (doi):

10.1038/s41467-018-06703-2

Reference (PMID):

30352999

PZ-2891

Probe Availability

Probe Information

Target Details

PANK, C20orf48, HARP, HSS, NBIA1, PKAN

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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PZ-2891

Probe Availability

Probe Information

Target Details

PANK, C20orf48, HARP, HSS, NBIA1, PKAN

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?