CC-292 (AVL-292)

Catalog No.S7173

CC-292 (AVL-292) is a covalent, orally active, and highly selective BTK inhibitor with IC50 of <0.5 nM, displaying at least 1400-fold selectivity over the other kinases assayed. Phase 1.

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CC-292 (AVL-292) Chemical Structure

CC-292 (AVL-292) Chemical Structure
Molecular Weight: 423.44

Validation & Quality Control

Quality Control & MSDS

Product Information

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Product Description

Biological Activity

Description CC-292 (AVL-292) is a covalent, orally active, and highly selective BTK inhibitor with IC50 of <0.5 nM, displaying at least 1400-fold selectivity over the other kinases assayed. Phase 1.
Targets BTK [1] YES [2] c-Src [2] BRK [2]

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IC50 <0.5 nM 723 nM 1.729 μM 2.43 μM
In vitro AVL-292 exhibits dose-dependent inhibition of Btk with EC50 of 8 nM and downstream BCR signaling components in Ramos cells. [1] AVL-292, by inhibiting BTK activities, further inhibits B cell proliferation with EC50 of 3 nM. [2]
In vivo In a collagen-induced arthritis mouse model, AVL-292 (3- 30 mg/kg, p.o.) dose-dependently inhibits the clinical signs of inflammatory disease, including reduction in joint and paw swelling and visible redness of the affected paws. [2]
Features Orally bioavailable BTK-selective inhibitor that has been tested in Phase I clinical trials for treatment of relapsed or refractory B-NHL, CLL and WM.

Protocol(Only for Reference)

Kinase Assay: [2]

Procedures for BTK OMNIA Assay The Omnia continuous read assay is performed essentially as described by the vendor. The assay conditions are: 40 μM ATP (1X KMATP), 10 μM Y5-Sox, and 10 nM BTK enzyme. Briefly, a substrate mix containing 1.13X ATP and the Y5 Sox substrate is first prepared in 1X Omnia Kinase Reaction Buffer (KRB) consisting of 20 mM Tris, pH 7.5, 5 mM MgCl2, 1 mM EGTA, 5 mMβ-glycerophosphate, 5% glycerol, and 0.2 mM DTT. For IC50 measurements, 5 μL of enzyme are incubated with serially diluted (3-fold) compounds prepared in 50% DMSO in a Corning (#3574) 384-well, white, non-binding surface microtiter plate at 25°C for 30 min. Kinase reactions are started with the addition of 45 μL of the ATP/Y5 substrate mix and monitored at λex360/λem485 in a Synergy 4 plate reader for 60 minutes. Progress curves from each well are examined for linear reaction kinetics and fit statistics. Initial velocity from each reaction is determined from the slope of a plot of relative fluorescence units versus time and then plotted against inhibitor concentration to estimate IC50 using the Response, Variable Slope model in GraphPad Prism from GraphPad Software.

Cell Assay: [2]

Cell lines Human B cells
Concentrations ~1000 nM
Incubation Time 72 hours
Method A suspension of resting purified naïve human B cells isolated by negative selection in RPMI is prepared at 0.4–0.5 × 106 cells/ml. Cells are mixed together with α-human IgM (final concentration of 5 μg/ml in each well) and vehicle (dimethyl sulfoxide) or AVL-292 (final concentrations of 0.01, 0.1, 1.0, 10.0, 100.0, or 1000 nM per well) and seeded in a 96-well plate. Cells are incubated for 56 hours in a humidified incubator maintained at 37°C and 5% CO2. 3H-Thymidine is added (final concentration of 1 μCi in each well) and cells are incubated overnight, harvested, and measured for 3H incorporation. Experiments are performed in triplicate.

Animal Study: [2]

Animal Models Collagen-induced arthritis mouse model
Formulation
Dosages ~30 mg/kg
Administration Oral administration

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Evans E, et al. ASH Annual Meeting, 2011 San Diego, CA.

[2] Evans EK, et al. J Pharmacol Exp Ther. 2013, 346(2), 219-228.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02433457 Completed Healthy Volunteers Celgene Corporation|Celgene May 2014 Phase 1
NCT02031419 Recruiting Lymphoma, Large B-Cell, Diffuse Celgene Corporation December 2013 Phase 1
NCT01975610 Active, not recruiting Rheumatoid Arthritis Celgene Corporation October 2013 Phase 2
NCT01766583 Active, not recruiting Relapsed/Refractory B-cell Lymphoma The Lymphoma Academic Research Organisation|Celgene Corpo  ...more The Lymphoma Academic Research Organisation|Celgene Corporation February 2013 Phase 1
NCT01732861 Active, not recruiting Leukemia Lymphocytic Chronic B-Cell Celgene Corporation December 2012 Phase 1

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Chemical Information

Download CC-292 (AVL-292) SDF
Molecular Weight (MW) 423.44
Formula

C22H22FN5O3

CAS No. 1202757-89-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms CC-292,LMK-435
Solubility (25°C) * In vitro DMSO 85 mg/mL (200.73 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2-Propenamide, N-[3-[[5-fluoro-2-[[4-(2-methoxyethoxy)phenyl]amino]-4-pyrimidinyl]amino]phenyl]-

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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