A-1155463

Reagent Authentication Certificate:

Chemical Probes Portal A-1155463.pdf

Protein target name:

BCLXL

Mechanism of action:

BH3 mimetic

Recommended Concentration for use in cells:

50-500 nM

Probe Availability

MedChem Express (1235034-55-5)

Abcam (1235034-55-5)

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Apotosis regulator

Subclass:

BCL2 family

HUGO symbol:

BCL2L1

Entrez gene ID:

598

Target alias:

BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

Chemical Probes Portal ID:

CPP1285

PubChem CID:

59447577

ChEMBL ID:

CHEMBL3342332

SMILES string:

CN(C)CC#CC1=CC(=C(C=C1)OCCCC2=C(N=C(S2)N3CCC4=CC=CC(=C4C3)C(=O)NC5=NC6=CC=CC=C6S5)C(=O)O)F

InChi Key:

SOYCFODXNRVBTI-UHFFFAOYSA-N

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6)  12.90 (s, 1H), 10.23 (s, 1H), 8.04 (d, J=7.32 Hz, 1H), 7.80 (d, J=8.24 Hz, 1H), 7.67 (d, J=7.32 Hz, 1H), 7.41 (m, 6H), 7.18 (t, J=8.70 Hz, 1H), 4.83 (s, 2H), 4.30 (s, 2H), 4.10 (t, J=6.26 Hz, 2H), 3.72 (t, J=5.95 Hz, 2H), 3.18 (t, J=7.48 Hz, 2H), 3.03 (t, J=5.95 Hz, 2H), 2.87 (s, 6H), 2.04 (m, 2H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

<0.01 nM

Potency assay:

Time-resolved, flourecence resonance energy transfer (TR-FRET) assays

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

4QVX

Structure-activity relationship:

Yes, see PMID: 25313317

Off target activity

Potency (off target):

Off target protein and potency:

BCL2: 80 nM, BCLW: 19 nM, MCL1: >440 nM

Potency assay (off target):

TR-FRET assays

In cell validation

On target activity in cells

Potency in cells:

EC50

8 nm

Potency assay (cells):

In Mcl1-/- mouse embryonic fibroblasts, A-1155463 inhibited cell proliferation. In H146 cells, A-1155463 inhibited BCLXL-dependent proliferation (EC50=65 nM).

In vivo validation

Organism:

SCID beige mice

Dose:

5 mg/kg

Route of delivery:

Intraperitoneal

Cmax:

1.8 uM

Tmax:

1 h

Organ of Interest

Organ (O):

Platelets, tumor xenografts

Target engagement assay:

In mice treated with A1155463, platelet counts declined within 6 hours of dosing and rebounded by 72 hours. In mice with H146 tumor xenografts, A1155463 inhibited tumor growth.

Primary Reference

Reference (doi):

10.1021/ml5001867

Reference (PMID):

25313317

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This is a very promising probe.

This probe is a selective picomolar inhibitor of BCL-XL. I recommend to use this probe to interrogate BCL-XL target in cells. It should be used in combination with ABT-199 (a selective inhibitor of BCL-2) to decouple BCL-XL and BCL-2 pathways. One concern, however, is that the molecule binds BCL-W (Ki=19 nM), and yet it inhibits H146 cells in 10% human serum with EC50=65 nM, which is close to Ki for BCL-W. Thus, BCL-W is a potential off target. As for in vivo use, this probe may be used with caution since its tissue and organ distribution were not reported. It does affect platelet counts (dependence on BCL-XL).

A-1155463

Probe Availability

Probe Information

Target Details

BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Search form

A-1155463

Probe Availability

Probe Information

Target Details

BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?