Home PI3K/Akt/mTOR PI3K Hämmare Eganelisib (IPI-549)

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Eganelisib (IPI-549) PI3Kγ-hämmare

Kat.nr.: S8330

Eganelisib (IPI-549), en potent hämmare av PI3K-γ med >100-faldig selektivitet jämfört med andra lipid- och proteinkinaser, har ett biokemiskt IC50-värde för PI3K-γ på 16 nM.
Eganelisib (IPI-549) PI3K Hämmare Chemical Structure

Kemisk struktur

Molekylvikt: 528.56

Hoppa till

Kvalitetskontroll (Quality Control)

Batch: Renhet: 99.98%
99.98

Cellodling, behandling & arbetskoncentration
(Cell Culture, Treatment & Working Concentration)

Cellinjer Analystyp Koncentration Inkubationstid Formulering Aktivitetsbeskrivning PMID
Sf9 Function assay Binding affinity to human recombinant full length N-terminal His-tagged PI3Kgamma expressed in Sf9 insect cells by equilibrium fluorescence titration analysis, Kd = 0.00029 μM. 27660692
RAW264.7 Function assay 30 mins Inhibition of PI3Kgamma in C5a-stimulated mouse RAW264.7 cells assessed as reduction in AKT phosphorylation at S473 incubated for 30 mins followed by stimulation with C5a for 3 mins by ELISA, IC50 = 0.0012 μM. 27660692
Sf9 Function assay 15 mins Inhibition of human recombinant full length N-terminal His-tagged PI3Kgamma expressed in Sf9 insect cells using diC8PIP2 as substrate incubated for 15 mins followed by substrate addition measured after 2 hr by ADP-Glo luminescence assay, IC50 = 0.016 μM. 27660692
Sf9 Function assay Binding affinity to human recombinant full length N-terminal His6-tagged PI3K p110alpha/p85alpha coexpressed in baculovirus infected Sf9 insect cells by equilibrium fluorescence titration analysis, Kd = 0.017 μM. 27660692
Sf9 Function assay Binding affinity to human recombinant full length N-terminal GST-tagged PI3K p110delta/p85alpha coexpressed in baculovirus infected Sf9 insect cells by equilibrium fluorescence titration analysis, Kd = 0.023 μM. 27660692
Sf9 Function assay Binding affinity to human recombinant full length N-terminal His6-tagged PI3K p110beta/p85alpha coexpressed in baculovirus infected Sf9 insect cells by equilibrium fluorescence titration analysis, Kd = 0.082 μM. 27660692
Raji Function assay 30 mins Inhibition of PI3Kdelta in IgM-stimulated human Raji cells assessed as reduction in AKT phosphorylation at S473 incubated for 30 mins followed by stimulation with IgM for 30 mins by ELISA, IC50 = 0.18 μM. 27660692
786-O Function assay 30 mins Inhibition of PI3Kbeta in human 786-O cells assessed as reduction in AKT phosphorylation at S473 after 30 mins by ELISA, IC50 = 0.24 μM. 27660692
SKOV-3 Function assay 30 mins Inhibition of PI3Kalpha in human SKOV-3 cells assessed as reduction in AKT phosphorylation at S473 after 30 mins by ELISA, IC50 = 0.25 μM. 27660692
Sf9 Function assay 15 mins Inhibition of human recombinant full length N-terminal His6-tagged PI3K p110alpha/p85alpha coexpressed in baculovirus infected Sf9 insect cells using diC8PIP2 as substrate incubated for 15 mins followed by substrate addition measured after 2 hr by ADP-Glo, IC50 = 3.2 μM. 27660692
Sf9 Function assay 15 mins Inhibition of human recombinant full length N-terminal His6-tagged PI3K p110beta/p85alpha coexpressed in baculovirus infected Sf9 insect cells using diC8PIP2 as substrate incubated for 15 mins followed by substrate addition measured after 2 hr by ADP-Glo , IC50 = 3.5 μM. 27660692
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Kemisk information, lagring & stabilitet (Chemical Information, Storage & Stability)

Molekylvikt 528.56 Formel

C30H24N8O2

 Lagring (från mottagningsdatumet)
CAS-nr 1693758-51-8 Ladda ner SDF Lagring av stamlösningar

Synonymer N/A Smiles CC(C1=CC2=C(C(=CC=C2)C#CC3=CN(N=C3)C)C(=O)N1C4=CC=CC=C4)NC(=O)C5=C6N=CC=CN6N=C5N

Löslighet (Solubility)

In vitro
Batch:

DMSO : 100 mg/mL (189.19 mM)
(Fuktkontaminerad DMSO kan minska lösligheten. Använd färk, vattenfri DMSO.)

Water : ˂1 mg/mL

Ethanol : ˂1 mg/mL

Molaritetsräknare

Massa Koncentration Volym Molekylvikt
Utspädningsräknare Molekylviktsräknare

In vivo
Batch:

In vivo-formuleringsräknare (Klar lösning)

Steg 1: Ange information nedan (Rekommenderas: Ett extra djur för att ta hänsyn till förluster under experimentet)

mg/kg g μL

Steg 2: Ange in vivo-formuleringen (Detta är endast räknaren, inte formuleringen. Vänligen kontakta oss först om det inte finns någon in vivo-formulering i löslighetsavsnittet.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Beräkningsresultat:

Arbetskoncentration: mg/ml;

Metod för att bereda DMSO-stamlösning: mg substans förlöst i μL DMSO ( Stamlösningskoncentration mg/mL, Vänligen kontakta oss först om koncentrationen överskrider DMSO-lösligheten för denna batch av substansen. )

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedanμL PEG300, blanda och klarna, tillsätt sedanμL Tween 80, blanda och klarna, tillsätt sedan μL ddH2O, blanda och klarna.

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedan μL Majsolja, blanda och klarna.

Obs: 1. Se till att vätskan är klar innan du tillsätter nästa lösningsmedel.
2. Se till att tillsätta lösningsmedlet/lösningsmedlen i ordning. Du måste se till att lösningen som erhålls i föregående tillsats är en klar lösning innan du fortsätter att tillsätta nästa lösningsmedel. Fysiska metoder som vortex, ultraljud eller varmt vattenbad kan användas för att underlätta upplösningen.

Verkningsmekanism (Mechanism of Action)

Targets/IC50/Ki
PI3Kγ
(Cell-free assay)
16 nM
In vitro
Eganelisib (IPI-549) is found to be a remarkably tight binder to PI3K-γ with a Kd of 290 pM and >58-fold weaker affinity for other Class I PI3K isoforms. It does not significantly inhibit a panel of 468 mutant and nonmutant protein and lipid kinases (including Class II PI3K isoforms) at 1 μM. In PI3K-α, -β, -γ, and -δ dependent cellular phospho-AKT assays, this compound demonstrates excellent PI3K-γ potency (IC50 = 1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold). Furthermore, it dose dependently inhibits PI3K-γ-dependent bone marrow-derived macrophage (BMDM) migration in vitro. It is also found to be selective against a panel of 80 GPCRs, ion channels, and transporters at 10 μM. In vitro, IPI-549 shows moderate to high cell permeability across Caco-2 cell monolayers, is slowly metabolized in cultured hepatocytes (t1/2 > 360 min), and demonstrates IC50s greater than 20 μM for the CYP isoforms tested (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4).
In vivo
Eganelisib (IPI-549) has excellent oral bioavailability, low clearance, and distributes into tissues with a mean volume of distribution of 1.2 L/kg in vivo (mice, rats, dog, and monkeys). It has a favorable pharmacokinetic profile to allow potent and selective inhibition of PI3K-γ in vivo. This compound can significantly reduce neutrophil migration in a dose-dependent manner in mouse model when administered orally at all of the tested doses. In addition, it has been shown to inhibit tumor growth in murine syngeneic models through alteration of immune cells in the tumor microenvironment.
Referenser

Applikationer (Applications)

Metoder Biomarkörer Bilder PMID
Western blot p-AKT / AKT / p-p65 / p65
S8330-WB1
27642729

Klinisk prövningsinformation (Clinical Trial Information)

(data från https://clinicaltrials.gov, uppdaterad den 2024-05-22)

NCT-nummer Rekrytering Tillstånd Sponsor/Samarbetspartners Startdatum Faser
NCT03980041 Completed
Bladder Cancer|Urothelial Carcinoma|Solid Tumor|Advanced Cancer
Infinity Pharmaceuticals Inc.|Bristol-Myers Squibb
 September 25 2019 Phase 2
NCT02637531 Unknown status
Advanced Solid Tumors (Part A/B/C/D)|Non-small Cell Lung Cancer (Part E)|Melanoma (Part E)|Squamous Cell Cancer of the Head and Neck (Part E)|Triple Negative Breast Cancer (Part F)|Adrenocortical Carcinoma (Part G)|Mesothelioma (Part G)|High-circulating Myeloid-derived Suppressor Cells (Part H)
Infinity Pharmaceuticals Inc.
 December 2015 Phase 1