LNP023

Protein target name:

CFB

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Protease

Subclass:

Serine Protease

HUGO ID:

HGNC:1037

Entrez gene ID:

629

UNIPROT ID:

P00751

Target alias:

BF; FB; BFD; GBG; CFAB; CFBD; PBF2; AHUS4; FBI12; H2-Bf; ARMD14

Probe Details

Chemical Probes Portal ID:

CPP1866

Probe alias:

LNP-023, cod41, Iptacopan

PubChem CID:

90467622

ChEMBL ID:

CHEMBL4594448

SMILES string:

O=C(O)C1=CC=C([C@H]2N(CC3=C(OC)C=C(C)C4=C3C=CN4)CC[C@H](OCC)C2)C=C1

InChi Key:

RENRQMCACQEWFC-UGKGYDQZSA-N

Physico-chemical properties

NMR:

1H NMR (400 MHz, D2O) δ 7.96 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 6.66 (s, 1H), 6.20 (s, 1H), 4.62–4.47 (m, 1H), 4.06 (d, J = 13.2 Hz, 1H), 3.97–3.76 (m, 2H), 3.66–3.48 (m, 5H), 3.43–3.29 (m, 1H), 3.26–3.15 (m, 1H), 2.35 (s, 3H), 2.31–2.11 (m, 2H), 2.00 (d, J = 15.4 Hz, 1H), 1.93–1.74 (m, 1H), 1.25–1.07 (m, 3H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

KD, IC50

7.9, 12 nM

Potency assay:

SPR, Half-maximal inhibition of human FB in TR-FRET based competition binding assay (FB-comp)

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

6RAV

Structure-activity relationship:

yes, check DOI: 10.1021/acs.jmedchem.9b01870

Off target activity

Probe Selectivity in Vitro:

IC50 values of >30 μM across a panel of 41 human proteases, including the AP protein factor D (>100 μM)

In cell validation

On target activity in cells

Potency in cells:

IC50

130 nM (h)110 nM (m)150 nM (h. whole blood)

Potency assay (cells):

inhibition of AP-induced MAC formation in 50% human and mouse serum

Off target activity in cells

Probe Selectivity in Cell:

LNP023 provided IC50 values of >30 μM across an internal panel of ∼110 enzymes, receptors, and ion channels, including hERG and adrenergic receptors α1a and α2c

In vivo validation

Organism:

C57BL/6 miceRatDog

Dose:

1 to 30 mg/Kg (R)0.1 to 10 mg/Kg (D)1 (IV), 10 (PO) mg/Kg (m)

Route of delivery:

OralIntravenous

Plasma half life:

7 (R) 5.6 (D) 7.2 (m) h

Systemic clearance:

8 (R), 2 (D), 16 (m) mL/min/Kg

Fraction of probe bound to plasma protein:

57-74% in all species

Cmax:

410 (R), 2200 (D), 224 (m) nM

Tmax:

2 (R), 0.8 (D) h

Primary Reference

Reference (doi):

10.1073/pnas.1820892116 10.1021/acs.jmedchem.9b01870 10.1053/j.seminhematol.2018.02.002

Reference (PMID):

30926668 32073845 30032754

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

1 review(s)

Rating for use in Model Organisms

1 review(s)

SAB Members

SAB Comments

LNP023 is a first in class, potent reversible inhibitor of the serine protease factor B (FB). This protease is a key component of the alternative complement pathway. This pathway is dysregulated in a number of diseases, and a number of targets in the pathway are active subjects of drug discovery programs. The compound was optimized using structure-based drug design and a number of useful crystal structures have been deposited. LPN023 has IC50 values >30 micromolar for 41 other proteases tested. The selectivity is likely due to unique features of the FB active site. It also is inactive (IC50>30 micromolar) across a panel of 110 enzymes, receptors, and ion channels. It exhibits the expected on-target pharmacology and in vivo activity. Phase 1 trials have been completed and it is in phase 2 trials for several diseases.

Mar 12 2021 - 10:25am

LNP023

Probe Availability

Probe Information

Target Details

BF; FB; BFD; GBG; CFAB; CFBD; PBF2; AHUS4; FBI12; H2-Bf; ARMD14

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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LNP023

Probe Availability

Probe Information

Target Details

BF; FB; BFD; GBG; CFAB; CFBD; PBF2; AHUS4; FBI12; H2-Bf; ARMD14

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?