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.
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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 |
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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
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