Home PI3K/Akt/mTOR PI3K inhibitor Seletalisib (UCB-5857)

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Seletalisib (UCB-5857) PI3K inhibitor

Cat.No.S8560

Seletalisib (UCB-5857) is a novel small-molecule inhibitor of PI3Kδ with an IC50 value of 12 nM, and it shows significant selectivity to PI3Kδ with respect to the other class I PI3K isoforms (between 24- and 303-fold).
Seletalisib (UCB-5857) PI3K inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 482.85

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Quality Control

Batch: S856001 DMSO]97 mg/mL]false]Ethanol]97 mg/mL]false]Water]Insoluble]false Purity: 99.07%
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99.07

Solubility

In vitro
Batch:

DMSO : 97 mg/mL (200.89 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 97 mg/mL

Water : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 482.85 Formula

C23H14ClF3N6O

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1362850-20-1 -- Storage of Stock Solutions

Synonyms N/A Smiles C1=CC2=CC(=C(N=C2C(=C1)Cl)C3=C[N+](=CC=C3)[O-])C(C(F)(F)F)NC4=NC=NC5=C4N=CC=C5

Mechanism of Action

Targets/IC50/Ki
PI3Kδ
(Cell-free assay)
12 nM
PI3Kγ
(Cell-free assay)
282 nM
In vitro

Seletalisib (UCB-5857) is a potent, ATP-competitive, and selective PI3Kδ inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, it inhibited N-formyl peptide-stimulated but not phorbol myristate acetate–stimulated superoxide release from human neutrophils, consistent with a PI3Kδ-specific activity. Findings from cellular assays of adaptive immunity demonstrated that this compound blocks human T-cell production of several cytokines from activated T-cells. Additionally, it inhibited B-cell proliferation and cytokine release. In human whole blood assays, the inhibitor suppressed CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. From 239 kinases screened, seletalisib at a concentration of 10 μM showed no inhibitory activity greater than 47% (MAP4K4) against non-PI3K kinase enzymes. Against nonkinase enzymes, it showed weak activities against phosphodiesterase (PDE)3A, PDE2A1, and PDE4D2, with inhibition varying between 32 and 74% at 10 μM. When screened at a concentration of 10 μM against 55 receptors and ion channels, the highest inhibitory activity observed was 20%. One receptor, neuropeptide Y receptor (Y1) showed 54% activation. In vitro receptor binding and enzyme assays across a broad range of target classes showed that it is selective for PI3Kδ. The compound potently inhibited the phosphorylation of AKT following anti-IgM stimulation of the BCR on Ramos cells with an IC50 of 15 nM. When profiled in a wide range of primary cell assay systems, including fibroblasts, epithelial, endothelial and vascular smooth muscle cells, it showed significant activity only in those systems containing lymphocytes, demonstrating its functional selectivity towards PI3Kδ-expressing cells.
Kinase Assay
In Vitro Kinase Activity Assays and Off-Target Profiling
The activities of seletalisib (UCB-5857) and the pan-PI3K inhibitor UCB1370037 were tested in biochemical kinase assays of the PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ (manufactured in-house) isoforms. Competitive time-resolved (TR) fluorescence resonance energy transfer (FRET) assays using a four-step PI3K assay reagent kit were performed. In this assay, PI3K activity is measured by the detection of phosphatidylinositol triphosphate (PIP3) as follows: A complex is formed between biotinylated PIP3 and a glutathione S-transferase (GST)-tagged pleckstrin homology–domain protein, which are detected by streptavidin-allophycocyanin (APC) and europium-labeled anti-GST antibody, respectively. Proximity of the two fluorophores results in a stable TR-FRET signal. The production of unlabeled PIP3 by PI3K in the kinase reaction results in competitive inhibition of the complex and therefore the FRET signal. Briefly, 2 μl of compound was added to wells containing 8 μl of a mixture containing phosphatidylinositol bisphosphate (PIP2) substrate and ATP, before addition of 10 μl of PI3K (prediluted to the required concentration). The final assay concentrations of ATP and PIP2 substrate were 2 μM and 10 μM, respectively. The final assay concentration of PI3K enzymes was 1–8 nM depending on batch activity. The final assay concentration of DMSO was 2.0%. The plate was incubated at room temperature for 30 minutes before addition of stop buffer and detection buffer according to manufacturer instructions, and the plate was then incubated for a further 6 hours at room temperature. TR-FRET measurements were performed on an Analyst GT plate reader. The ATP concentration dependence of the activity of this compound against PI3Kδ was established by running the assay in the presence of varying ATP concentrations (2, 40, 200, and 1000 μM). The final assay concentrations of PI3Kδ and PIP2 substrate in these assays were 1 nM and 25 μM, respectively.
In vivo

Seletalisib (UCB-5857) shows dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Analysis of the relationship between inhibition of IL-2 release and its blood concentration, using combined data across experiments, demonstrated that this compound has potent in vivo effects with an estimated IC50 value of <10 nM. In first-in-man studies, mean plasma concentration-time profiles increased with increasing dose after single and multiple dosing, with no major deviations from dose proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic (PK) profile) and apparent t1/2 values (approx. 20h) were supportive of once-daily dosing.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02207595 Completed
Healthy Volunteers
UCB Celltech|Parexel|UCB Pharma
 August 2014 Phase 1
NCT02303509 Completed
Psoriasis
UCB Pharma|Parexel
 August 2013 Phase 1

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