A-1331852

Protein target name:

BCL2L1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 100 nM

Probe Availability

MedChemExpress

Selleck Biochemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

BCL2 Family

Subclass:

Apoptosis Regulator

HUGO ID:

HGNC:992

Entrez gene ID:

598

UNIPROT ID:

Q07817

Target alias:

BCLX; BCL2L; Bcl-X; PPP1R52; BCL-XL/S

Probe Details

Chemical Probes Portal ID:

CPP2208

Probe alias:

cpd 13

PubChem CID:

71565985

ChEMBL ID:

CHEMBL3793424

SMILES string:

O=C(C1=NC(N2CC3=C(C=CC=C3C(NC4=NC5=CC=CC=C5S4)=O)CC2)=CC=C1C6=C(C)N(CC7(C8)CC9CC8CC(C9)C7)N=C6)O

InChi Key:

QCQQONWEDCOTBV-UHFFFAOYSA-N

Orthogonal probe:

A-1155463DT-2216WEHI-539

Physico-chemical properties

NMR:

1H NMR (400 MHz, dimethylsulfoxide- d6) δ ppm 12.82 (br s, 2 H), 8.18 – 7.92 (m, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 7.62 (dd, J = 7.6, 1.5 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.48 - 7.41 (m, 2 H), 7.40 – 7.31 (m, 2 H), 7.27 (s, 1 H), 6.94 (d, J = 8.9 Hz, 1 H), 4.95 (s, 2 H), 3.88 (t, J = 5.9 Hz, 2 H), 3.70 (s, 2 H), 3.01 (t, J = 6.0 Hz, 2 H), 2.10 (s, 3 H), 1.94 - 1.89 (m, 3 H), 1.70 – 1.44 (m, 12 H).

13C NMR (101 MHz, dimethylsulfoxide-d6) δ ppm 168.42, 167.64, 158.41, 155.92, 148.53, 148.39, 140.81, 136.99, 136.54, 136.46, 133.76, 131.87, 131.51, 131.49, 126.57, 126.24, 126.21, 123.76, 121.76, 120.53, 115.58, 115.43, 107.98, 59.85, 44.92, 41.82, 40.12, 36.34, 35.06, 28.11, 27.73, 24.97, 10.53, 1.17.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.01 nM

Potency assay:

BCL-XL TR-FRET

Structure-activity relationship:

yes

Off target activity

Potency assay (off target):

TR-FRET

Probe Selectivity in Vitro:

Bcl-W 4 nM (Ki), Bcl-2 6 nM (Ki), Mcl-1 142 nM (Ki)

In cell validation

On target activity in cells

Potency in cells:

EC50

6.3 nM

Potency assay (cells):

BCellTiter-Glo cell viability assay; induction of apoptosis in BCL-XL–dependent Molt-4 cells, does not affect MEF cells lacking BAK or BAX CL-XL–BIM and BCL-2–BIM complexes in Molt-4 cells

Off target activity in cells

Probe Selectivity in Cell:

RSA;11 EC50 >5000 nM

In vivo validation

Organism:

MouseRat

Dose:

5-30 mg/Kg

Route of delivery:

Oral

Plasma half life:

3.9 (R), 2.4 (M) h

Systemic clearance:

0.08 (R), 0.22 (M) L/h/Kg

Cmax:

1.97 (R), 1.46 (M) uM

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.9b00568 10.1126/scitranslmed.aaa4642

Reference (PMID):

33062160 25787766

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

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

In vitro selectivity within the target family is good but no wider profiling is available. There are indications on target engagement based on knock-out experiments as measured by cell viability, but proof of direct in cell target engagement is lacking.

Mar 20 2021 - 8:30am

Targeting BCL´s with a small molecule is challenging. The interaction of Bcl-xL with A-1331852 in complex (PDB: 6VWC) should be added to the review form. There is a significant amount of data showing the activity of A-1331852 in a range of cell-lines and xenograft models (10.1126/scitranslmed.aaa4642). However, there is insufficient experimental data showing its overall profile against other protein targets. A search in PubChem for A-1331852 only yielded BioAssay Results for the BCL proteins. Therefore, the major concern with A-1331852 relates to its off-target affects against for example kinases, GPCRs, nuclear receptors, ion-channels, proteases, etc. Without such a comprehensive profile, the observations of A-1331852 in cell-based assays may be due its poly-pharmacology. Once such data is made available, A-1331852 is likely to meet the criteria for use as a Probe in cells.

Mar 24 2021 - 10:23am

A-1331852

Probe Availability

Probe Information

Target Details

BCLX; BCL2L; Bcl-X; PPP1R52; BCL-XL/S

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-1331852

Probe Availability

Probe Information

Target Details

BCLX; BCL2L; Bcl-X; PPP1R52; BCL-XL/S

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?