Spebrutinib (AVL-292) is an orally available and highly selective covalent inhibitor of Bruton's tyrosine kinase (Btk) that is currently undergoing Phase 1b clinical development for CLL and B-NHL. AVL-292 selectively and covalently bonds to Btk to inactivate and silence its activity. Spebrutinib (AVL-292) inhibited osteoclast function and reduced osteoclast-stimulated proliferation of MM cells. Spebrutinib (AVL-292) was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. The ongoing phase Ib clinical trial of AVL-292 is being conducted in patients with B-cell malignancies, including B-cell NHL, CLL, and WM.
 |
Source | Allergy (2017). Figure 1. AVL-292 |
| Method | flow cytometry | |
| Cell Lines | HMC-1 cells, and KU812 cells | |
| Concentrations | 0.01-10 μmol/L | |
| Incubation Time | 4 hours | |
| Results | We found that dasatinib, ibrutinib, AVL-292, and CNX-774 counteract anti-IgE-induced expression of pBTK in BA |
 |
Source | Allergy (2017). Figure 5. AVL-292 |
| Method | proliferation assay | |
| Cell Lines | HMC-1 cells and KU812 cells | |
| Concentrations | 0.001-10 μmol/L | |
| Incubation Time | 48 h | |
| Results | As determined by 3H-thymidine uptake, ibrutinib, AVL-292, and P505-15 showed no significant effects on proliferation of HMC-1.1, HMC-1.2, and KU812 cells unless high concentrations (≥1 μmol/L) were applied |
| Cell Experiment | |
|---|---|
| Cell lines | naïve human B cells |
| Preparation method | Immunoblot Analysis. Cells were incubated in serum-free RPMI media for 1–1.5 hours. Isolated human B cells were incubated with CC-292 at a final concentration of 0.001, 0.01, 0.1 and 1 μM. Ramos cells were incubated with 0.1 nM–3 μM CC-292. Cells were then incubated in the presence of compound for 1 hour at 37°C. Following incubation, cells were centrifuged and resuspended in 100 μl of serum-free RPMI and BCR was stimulated with addition of 5 μg/ml α-human IgM. Samples were centrifuged, washed in phosphate-buffered saline (PBS), and lysed in 100 μl of Cell Extraction Buffer [cat. no. FNN0011; Life Technologies (Invitrogen), Carlsbad, CA] plus 1:10 (v/v) PhosSTOP Phosphatase Inhibitor (Roche, Basel, Switzerland) and 1:10 (v/v) Complete Protease Inhibitor (cat. no. 11836145001; Roche). Antibodies used for immunoblot analysis include P-PLCγ2 [cat. no. 3872; Cell Signaling Technology, Beverly, MA (CST)], PLCγ2 (3871; CST), Syk (2712; CST), P-Syk (2710; CST), Btk (cat. no. 611116; BD Biosciences, Franklin Lakes, NJ), P-Btk (cat. no. 2207-1; Epitomics, Berlingame, CA), and Tubulin (cat. no. T6199; Sigma-Aldrich, St. Louis, MO). Membranes were scanned on a Li-Cor Odyssey scanner using infrared fluorescence detection (Li-Cor Biosciences, Lincoln, NB).. |
| Concentrations | 0.001, 0.01, 0.1 and 1 μM |
| Incubation time | 1h |
| Animal Experiment | |
|---|---|
| Animal models | Collagen-Induced Arthritis Model |
| Formulation | not mentioned |
| Dosages | 10,30,50 mg/kg |
| Administration | oral |
| Molecular Weight | 423.44 |
| Formula | C22H22FN5O3 |
| CAS Number | 1202757-89-8 |
| Solubility (25°C) | DMSO 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[1] Danilo De Novellis, et al. The TKI Era in Chronic Leukemias
[2] Emanuela Grassilli, et al. p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors
| Related BTK Products |
|---|
| TAS5315
TAS5315 is a novel, irreversible covalent inhibitor of BTK for studies related to rheumatoid arthritis. |
| JS25
JS25 is a selective and covalent inhibitor of BTK that inactivates BTK with an IC50 value of 5.8 nM by chelating Tyr551. JS25 inhibits cancer cells proliferation, pronounces cell death, and promotes murine xenograft model of Burkitt’s lymphoma. JS25 effectively crosses the blood-brain barrier. |
| BGB-8035
BGB-8035 is an orally active, highly selective bruton's tyrosine kinase (BTK) inhibitor with IC50s of 1.1 nM, 99 nM, 621 nM for BTK, TEC, EGFR, respectively. BGB-8035 has antitumor and anti-arthritis activity. BGB-8035 has the potential for B-cell malignancies and autoimmune diseases research. |
| CHMFL-BTK-01
CHMFL-BTK-01 (compound 9) is a highly selective irreversible BTK inhibitor, with an IC50 of 7 nM. CHMFL-BTK-01 (compound 9) potently inhibited BTK Y223 auto-phosphorylation. |
| BTK inhibitor 17
BTK inhibitor 17 is a potent and orally active irreversible BTK inhibitor with an IC50 of 2.1 nM. BTK inhibitor 17 can be used for rheumatoid arthritis research. |
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2023 AbMole BioScience. All Rights Reserved.
