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Itraconazole Hedgehog/Smoothened inhibitor

Cat. No.: S2476

Itraconazole is a relatively potent inhibitor of CYP3A4 with IC50 of 6.1 nM, used as a triazole antifungal agent. This compound is a potent antagonist of the Hedgehog (Hh) signaling pathway. It also suppresses the growth of glioblastoma through induction of autophagy.
Itraconazole Hedgehog/Smoothened inhibitor Chemical Structure

Estructura química

Peso molecular: 705.65031

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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
human hepatocytes Function assay Inhibition of CYP3A4 in human hepatocytes using testosterone as substrate by HPLC/MS/MS method, IC50=0.07 μM
human HTLA cells Function assay 20 mins Inhibition of CX3CL1-stimulated CX3CR1 in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay, IC50=0.1 μM
LLC-PK1 epithelial cells Function assay Inhibition of P-glycoprotein, mouse L-mdr1a expressed in LLC-PK1 epithelial cells using calcein-AM polarisation assay, IC50=0.2 μM
human PBMC Cytotoxicity assay 72 h Cytotoxicity against human PBMC assessed as cell viability after 72 hrs by MTT assay, IC50=1.53 μM
Topp 3 cells Function assay Inhibition of human CYP51 expressed in Topp 3 cells by lanosterol demethylase assay, IC50=3.6 μM
human MRC5 cells Cytotoxicity assay Cytotoxicity against human MRC5 cells, CC50=49.33 μM
human HUVEC cells Function assay 2 μM 24 h Inhibition of VEGFR2 glycosylation in human HUVEC cells at 2 uM after 24 hrs by Western blot analysis
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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular 705.65031 Fórmula

C35H38Cl2N8O4

 Almacenamiento (Desde la fecha de recepción)
Nº CAS 84625-61-6 Descargar SDF Almacenamiento de soluciones madre

Sinónimos R 51211 Smiles CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 13 mg/mL (18.42 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Water : Insoluble

Ethanol : Insoluble

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
CYP3A4
(human liver microsomes)
6.1 nM
In vitro
Itraconazole is metabolized into hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). This compound is a substrate for CYP3A in vitro and to characterize the metabolites generated. It exhibits an unbound Km of 3.9 nM for CYP3A. Its metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself. This compound appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation. It is active against 60 clinical isolates of Aspergillus spp. with geometric mean (GM) MICs of 0.25 mg/mL. It acts primarily by impairing the synthesis of ergosterol, resulting in a defective fungal cell membrane with altered permeability and function. This chemical is effective for a wide variety of mycotic infections and some fungal meningeal infections. It has an affinity for mammalian cytochrome P-450 enzymes as well as for fungal P-450-dependent enzyme, and thus has the potential for clinically important interactions (e.g., astemizole, terfenadine, rifampin, oral contraceptives, H2 receptor antagonists, warfarin, cyclosporine).
In vivo
Itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model.
Referencias
  • [4] https://pubmed.ncbi.nlm.nih.gov/8083506/
  • [5] https://pubmed.ncbi.nlm.nih.gov/9594936/
  • [6] https://pubmed.ncbi.nlm.nih.gov/15242978/

Aplicaciones (Applications)

Métodos Biomarcadores Imágenes PMID
Western blot pACC / ACC / p-S6K / S6K GLI1 / GLI2 / p-AKT1 / AKT1 / Cyclin D1
S2476-WB1
28103683
Growth inhibition assay Cell viability
S2476-viability1
24905460

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
NCT05563766 Not yet recruiting
Esophageal Adenocarcinoma|Esophageal Squamous Cell Carcinoma|Gastroesophageal Junction Carcinoma
VA Office of Research and Development|Durham VA Health Care System|VA Palo Alto Health Care System|Portland VA Medical Center|VA Puget Sound Health Care System|Michael E. DeBakey VA Medical Center|VA Boston Healthcare System
 May 1 2024 Phase 2
NCT06357520 Recruiting
Healthy Participants
AstraZeneca
 April 16 2024 Phase 1
NCT06348888 Recruiting
Advanced Non-small Cell Lung Cancer|EGFR Mutation|HER2 Mutation|Healthy Volunteers
Bayer
 April 10 2024 Phase 1
NCT06362642 Recruiting
Healthy Volunteers
PMV Pharmaceuticals Inc
 March 28 2024 Phase 1

Preguntas frecuentes (Frequently Asked Questions)

Pregunta 1:
We are finding the best vehicle to administer it to mice. We want a mild vehicle (unlike DMSO) which resembles water, PBS, saline (for i.p/ injection) or methyl cellulose (for oral).

Respuesta:
We are not able to dissolve S2476 clearly without DMSO. For oral gavage, this compound can be dissolved in 1% CMC Na at 20mg/ml as a homogeneous suspension.