AVL-292

AVL-292 : ATP-competitive, covalent inhibitor of BTK

Structure

Information

  • BTK
  • ATP-competitive inhibitor, Covalent inhibitor

In Vitro Validations

Uniprot ID: Q06187
Target Class: Protein kinase
Target SubClass: TK
Potency: Kinact/KI
Potency Value: 7.69 x 10^4 per M per sec
Potency Assay: IC50 (app) < 0.5 nM
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Tyrosine-protein kinase BTK, AGMX1, BTK, BTK_HUMAN ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50(app) BMX 0.7 nM, ITK 36 nM, TEC 6.2 nM, TXK 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.
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SERP ratings and comments


SERP Ratings

In Cell Rating

SERP Comments:

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.

(last updated: 22 May 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP 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.

(last updated: 2 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 12 Apr 2017 )