AVL-292

Reagent Authentication Certificate:

Chemical Probes Portal AVL-292.pdf

Protein target name:

BTK

Mechanism of action:

ATP-competitive inhibitorCovalent inhibitor

Recommended Concentration for use in cells:

Up to 100 nM

Probe Availability

MedChem Express (1202757-89-8)

Cayman (1202757-89-8)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:1133

Entrez gene ID:

695

UNIPROT ID:

Q06187

Target alias:

AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA

Probe Details

Chemical Probes Portal ID:

CPP115

Probe alias:

Cc-292, Spebrutinib, AVL292

PubChem CID:

59174488

ChEMBL ID:

CHEMBL3301625

SMILES string:

COCCOC1=CC=C(C=C1)NC2=NC=C(C(=N2)NC3=CC(=CC=C3)NC(=O)C=C)F

InChi Key:

KXBDTLQSDKGAEB-UHFFFAOYSA-N

Orthogonal probe:

CGI1746GDC-0834

PAINs evaluation:

PAINs free. Note that no acrylamides were present in the HTS compounds originally used to define PAINS, so "PAINS-FREE" has little meaning here with respect to acrylamides

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Kinact/KI

7.69 x 10^4 per M per sec

Potency assay:

IC50 (app) < 0.5 nM

Off target activity

Potency (off target):

IC50(app)

Off target protein and potency:

BMX 0.7 nMITK 36 nMTEC 6.2 nMTXK 8.9 nM

Potency assay (off target):

High selectivity was noted against kinases with a comparable Cys (EGFR, ITK, JNK3). CC-292 was run in a kinase selectivity panel at Reaction Biology Corporation 47 (Malvern, PA) using HotSpotSM technology and radioisotope-based P81 filtration.

In cell validation

On target activity in cells

Potency in cells:

EC50

8 nM

Potency assay (cells):

Autophosphorylation in Ramos cells. EC50 for occupancy with a biotinylated derivative of AVL-292 was 6 nM.

Target engagement assay (cells):

Yes, occupancy with biotinylated derivative of AVL-292. Target occupancy was assessed for BTK (IC50 app = 0.5 nM), EGFR (IC50 app = 25 nM), SYK (IC50 app = 1,000 nM), LYN (IC50 app = 3,500 nM).

In vivo validation

Organism:

Mouse

Dose:

50 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

spleenjoint

Target engagement assay:

In the spleen, BTK occupancy was measured.

Primary Reference

Reference (doi):

10.1124/jpet.113.203489

Reference (PMID):

23709115

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

AVL-292 is a covalent inhibitor of BTK (IC50apparent <0.5 nM). Selectivity was >1000-fold based on IC50 determination against a panel of 47 kinases, and in two larger kinome panels (386 and 205 kinases, respectively) with ATP concentrations at the Km for each kinase, there was no significant inhibitory activity (< 50% inhibition at 1 µM). Additionally, 1 µM AVL-292 led to <40% inhibition of 82 non-kinase targets. Cellular activity was reported as EC50 = 6-8 nM. A pharmacodynamics marker for intracellular target engagement has been described, and target engagement was reported following oral administration to mice (3-30 mg/kg) and humans (2 mg/kg), with in vivo target engagement uncoupled from PK presumably due to the irreversible nature of the inhibitor.

Jun 11 2016 - 4:27am

This probe inhibits both BTK and EGFR, similar to ibrutinib. In cell based assays AVL-292 appears to have additional targets as it is cytotoxic to endothelial cells at 10 uM and active at 300 nM in human primary cell assays that do not express BTK. There are more potent and selective BTK inhibitors, such as GDC-0834.

Jun 11 2016 - 4:28am

AVL-292 is a covalent BTK inhibitor. Some selectivity data was provided demonstrating that the compound did inhibit other kinases under 100 nM (BMX, ITK, TEC, TXK) in a biochemical assay format. The authors did evaluate cellular inhibition of speciifc kinases that also had a cysteine in a homologous position and those cellular IC50's were in the micromolar range (EGFR, JAK3, ITK). This compound has been further tested in mice and then went into human clinical trials.

Apr 13 2017 - 11:47am

AVL-292

Probe Availability

Probe Information

Target Details

AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AVL-292

Probe Availability

Probe Information

Target Details

AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?