LYS006

Protein target name:

LTA4H

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 200 nM

Probe Availability

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

leukotriene A4 hydrolase, LTA4

Subclass:

Hydrolase

HUGO ID:

HGNC:6710

Entrez gene ID:

4048

UNIPROT ID:

P09960

Probe Details

Chemical Probes Portal ID:

CPP2275

Probe alias:

cpd (S)-22

PubChem CID:

118166566

SMILES string:

O=C(O)C[C@H](N)CN(N=N1)N=C1C2=CC=C(OC3=C(F)C=C(Cl)C=N3)C=C2

InChi Key:

ZEGMEJVULDALSH-NSHDSACASA-N

Control compound:

cpd 10

Physico-chemical properties

Solubility - preferred solvent:

663 uM

NMR:

1H NMR (600 MHz, CD3OD): δ 8.25–8.19 (m, 2H), 7.96 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 9.4, 2.2 Hz, 1H), 7.36–7.31 (m, 2H), 5.16 (d, J = 5.7 Hz, 2H), 4.30–4.26 (m, 1H), 2.95 (dd, J = 18.0, 5.9 Hz, 1H), 2.80 (dd, J = 17.9, 6.9 Hz, 1H).

13C NMR (151 MHz, CD3OD): δ 170.82, 164.79, 155.29, 150.09 (d, J = 11.8 Hz, 1C), 147.22 (d, J = 265 Hz, 1C), 139.86 (d, J = 5.9 Hz, 1C), 127.85 (2C), 126.00, 125.31 (d, J = 19.1 Hz, 1C), 123.50, 120.85 (2C), 52.93, 47.03, 33.17.

19F NMR (376 MHz, CD3OD): δ −135.63 (d, J = 9.4 Hz, 1F).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

0.12 nM

Potency assay:

LTA4H enzyme inhibition assay using Arg-AMC as substrate with <1 nM enzyme concentration

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

7AUZ

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

LYS006 shows an exquisite selectivity profile when tested at concentrations of ≥10 μM in binding or functional mode on a panel of >150 GPCRs, transporters, ion channels, nuclear receptors, and enzymes in vitro. Inhibitory activity of LYS006 against selected Zn-containing enzymes showed no IC50 < 30 uM.

In cell validation

On target activity in cells

Potency in cells:

IC50IC90

3.7 nM IC50, 27 nM IC90 (P), 53 nM IC50, 148 nM IC90 (W)

Potency assay (cells):

Human PBMC (P) and Whole Blood (W) ionophore stimulated LTB4 release assay with 4 h compound preincubation (Eicosanoid Release assay).

In vivo validation

Organism:

MouseRatDog

Dose:

0.1, 1, 3 (IV) mg/Kg, 0.3, 3, 10 (PO) mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

16.7±5.3 (M), 169 (R), 48.8±4.3 (D) h

Systemic clearance:

4.2 (M), 0.66 (R), 0.94 (D) mL/min/Kg

Cmax:

689±271 (M), 1240±232 (R), 306±60.3 (D) nM

Tmax:

0.25±0 (M), 4.0±0 (R), 5.0±1.7 (D) h

Vss:

2.15±0.78 (M), 3.29 (R), 3.81±0.460 (D) L/Kg

AUC:

1940±139 (M), 38500±6070 (R), 17600±1550 (D) nM*h

Bioavailability:

18.2±1.3 (M), 56.8±9.0 (R), 38.7±3.4 (D) %

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.0c01955

Reference (PMID):

33592148

LYS006

Probe Availability

Probe Information

Target Details

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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LYS006

Probe Availability

Probe Information

Target Details

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?