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Eganelisib (IPI-549) Inhibidor de PI3Kγ

Cat. No.: S8330

Un potente inhibidor de PI3K-γ con una selectividad >100 veces mayor sobre otras quinasas lipídicas y proteicas, Eganelisib (IPI-549) tiene una CI50 bioquímica para PI3K-γ de 16 nM.
Eganelisib (IPI-549) PI3K Inhibidor Chemical Structure

Estructura química

Peso molecular: 528.56

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Control de calidad (Quality Control)

Lote: Pureza: 99.98%
99.98

Cultivo celular, tratamiento y concentración de trabajo
(Cell Culture, Treatment & Working Concentration)

Líneas celulares Tipo de ensayo Concentración Tiempo de incubación Formulación Descripción de la actividad 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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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular 528.56 Fórmula

C30H24N8O2

 Almacenamiento (Desde la fecha de recepción)
Nº CAS 1693758-51-8 Descargar SDF Almacenamiento de soluciones madre

Sinónimos 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

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 100 mg/mL (189.19 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Water : ˂1 mg/mL

Ethanol : ˂1 mg/mL

Calculadora de Molaridad

Masa Concentración Volumen Peso molecular
Calculadora de Dilución Calculadora de Peso Molecular

In vivo
Lote:

Calculadora de formulación in vivo (Solución clara)

Paso 1: Introduzca la información a continuación (Recomendado: Un animal adicional para tener en cuenta la pérdida durante el experimento)

mg/kg g μL

Paso 2: Introduzca la formulación in vivo (Esto es solo la calculadora, no la formulación. Por favor, contáctenos primero si no hay una formulación in vivo en la sección de Solubilidad.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Resultados del cálculo:

Concentración de trabajo: mg/ml;

Método para preparar el líquido maestro de DMSO: mg fármaco predissuelto en μL DMSO ( Concentración del líquido maestro mg/mL, Por favor, contáctenos primero si la concentración excede la solubilidad del DMSO del lote del fármaco. )

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadirμL PEG300, mezclar y clarificar, luego añadirμL Tween 80, mezclar y clarificar, luego añadir μL ddH2O, mezclar y clarificar.

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadir μL Aceite de maíz, mezclar y clarificar.

Nota: 1. Por favor, asegúrese de que el líquido esté claro antes de añadir el siguiente disolvente.
2. Asegúrese de añadir el (los) disolvente(s) en orden. Debe asegurarse de que la solución obtenida, en la adición anterior, sea una solución clara antes de proceder a añadir el siguiente disolvente. Se pueden utilizar métodos físicos como el vórtice, el ultrasonido o el baño de agua caliente para ayudar a la disolución.

Mecanismo de acción (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.
Referencias

Aplicaciones (Applications)

Métodos Biomarcadores Imágenes PMID
Western blot p-AKT / AKT / p-p65 / p65
S8330-WB1
27642729

Información del ensayo clínico (Clinical Trial Information)

(datos de https://clinicaltrials.gov, actualizado el 2024-05-22)

Número NCT Reclutamiento Condiciones Patrocinador/Colaboradores Fecha de inicio Fases
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