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Alectinib (CH5424802) ALK Inhibidor

Name: Alectinib (CH5424802)
Brand: Selleck Chemicals
SKU: S2762
Rating: 5 (104 reviews)

Cat. No.: S2762

Alectinib es un potente inhibidor de ALK con un IC50 de 1,9 nM en ensayos sin células, sensible a la mutación L1196M y con mayor selectividad para ALK que PF-02341066, NVP-TAE684 y PHA-E429.

Alectinib (CH5424802) ALK Inhibidor Chemical Structure

Estructura química

Peso molecular: 482.62

Saltar a

Control de calidad (Quality Control)

Lote: Pureza: 99.95%

99.95

Dianas relacionadas	EGFR VEGFR FGFR PDGFR c-Met Src MEK CSF-1R HER2 FLT3
Otros ALK Inhibidores	TAE684 (NVP-TAE684) GSK1838705A Repotrectinib (TPX-0005) AZD3463 Ensartinib dihydrochloride AP26113-analog (ALK-IN-1) ASP3026 NVL-655 (Neladalkib) Envonalkib Belizatinib (TSR-011)

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
NCI-H2228	Kinase assay	~1 μM			prevents autophosphorylation of ALK	21575866
KARPAS-299	Growth inhibitory assay	~10 μM			IC50=3 nM	21575866
SR	Growth inhibitory assay	~10 μM			IC50=6.9 nM	21575866
HDLM-2	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
NB-1	Growth inhibitory assay	~10 μM			IC50=4.5 nM	21575866
KELLY	Growth inhibitory assay	~10 μM			IC50=62 nM	21575866
SK-N-FI	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
NCI-H2228	Growth inhibitory assay	~10 μM			IC50=53 nM	21575866
Calu-3	Growth inhibitory assay	~10 μM			IC50=>10,000 nM	21575866
PC-1	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
NCI-H23	Growth inhibitory assay	~10 μM			IC50=3600 nM	21575866
Calu-1	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
NCI-H2009	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
NCI-H1993	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
MKN-45	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
SNU-5	Growth inhibitory assay	~10 μM			IC50=1800 nM	21575866
KATO-III	Growth inhibitory assay	~10 μM			IC50=7900 nM	21575866
SK-BR-3	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
BT-483	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
PC-3	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
22Rv1	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
U-87 MG	Growth inhibitory assay	~10 μM			IC50>10,000 nM	21575866
H3122	Growth inhibitory assay	~10 μM			IC50=33 nM	25096400
LC-2/ad	Apoptosis assay	~1 μM		DMSO	induces apoptosis	25349307
LC-2/ad	Function assay	~1 μM		DMSO	inhibits the MAPK signaling pathway	25349307
Ba/F3	Function assay	~1 μM		DMSO	suppresses phosphorylation of ERK and increases the abundance of BIM	25349307
SNU-2535	Growth inhibitory assay	~10 μM			IC50=33.1 nM	26849637
SNU-2535	Kinase assay	~1 μM			inhibits the phosphorylation of ALK and its downstream molecules ERK1/2 and AKT	26849637
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK C1156Y mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM.	26568289
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK S1206Y mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM.	26568289
Ba/F3	Function assay		72 hrs		Inhibition of wild type EML4-ALK (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM.	26568289
KARPAS299	Antiproliferative assay		96 hrs		Antiproliferative activity against human KARPAS299 cells after 96 hrs by cell counting assay, IC50 = 0.003 μM.	22225917
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK F1174L mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.003 μM.	26568289
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK G1269A mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.009 μM.	26568289
NCI-H3122	Antiproliferative assay		72 hrs		Antiproliferative activity against human NCI-H3122 cells after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.009 μM.	26568289
KARPAS299	Antiproliferative assay		72 hrs		Antiproliferative activity against human KARPAS299 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.015 μM.	27131066
NCI-H3122	Antiproliferative assay		72 hrs		Antiproliferative activity against human NCI-H3122 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0174 μM.	27131066
SUP-M2	Antiproliferative assay		72 hrs		Antiproliferative activity against human SUP-M2 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0179 μM.	27131066
NCI-H3122	Function assay		72 hrs		Inhibition of ALK expressed in human NCI-H3122 cells assessed as cell growth inhibition after 72 hrs by SRB/CCK-8 assay, IC50 = 0.019 μM.	27131066
NCI-H3122	Antiproliferative assay		72 hrs		Antiproliferative activity against ALK-dependent human NCI-H3122 cells after 72 hrs, IC50 = 0.019 μM.	26476749
SU-DHL1	Antiproliferative assay		72 hrs		Antiproliferative activity against human SU-DHL1 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0205 μM.	27131066
NIH/3T3	Antiproliferative assay		72 hrs		Antiproliferative activity against mouse NIH/3T3 cells expressing wild type EML4-ALK after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0323 μM.	27131066
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK 1151Tins mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.072 μM.	26568289
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK L1196M mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.09 μM.	26568289
NIH/3T3	Antiproliferative assay		72 hrs		Antiproliferative activity against mouse NIH/3T3 cells expressing EML4-ALK L1196 mutant after 72 hrs by SRB/CCK-8 assay, IC50 = 0.132 μM.	27131066
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK L1152R mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.169 μM.	26568289
Ba/F3	Function assay		72 hrs		Inhibition of EML4-ALK G1202R mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.207 μM.	26568289
DFCI114	Antiproliferative assay		72 hrs		Antiproliferative activity against human DFCI114 cells expressing EML4-ALK G1269A mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.207 μM.	26568289
CHLA20	Antiproliferative assay		72 hrs		Antiproliferative activity against human CHLA20 cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.43 μM.	26568289
Kelly	Antiproliferative assay		72 hrs		Antiproliferative activity against human Kelly cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.434 μM.	26568289
DFCI76	Antiproliferative assay		72 hrs		Antiproliferative activity against human DFCI76 cells expressing EML4-ALK L1152R mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.511 μM.	26568289
LAN5	Antiproliferative assay		72 hrs		Antiproliferative activity against human LAN5 cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.617 μM.	26568289
SMS-KCNR	Antiproliferative assay		72 hrs		Antiproliferative activity against human SMS-KCNR cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.765 μM.	26568289
SK-N-SH	Antiproliferative assay		72 hrs		Antiproliferative activity against human SK-N-SH cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.872 μM.	26568289
SH-SY5Y	Antiproliferative assay		72 hrs		Antiproliferative activity against human SH-SY5Y cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 1.15 μM.	26568289
SK-N-BE(2)	Antiproliferative assay		72 hrs		Antiproliferative activity against human SK-N-BE(2) cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 1.554 μM.	26568289
LAN1	Antiproliferative assay		72 hrs		Antiproliferative activity against human LAN1 cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.004 μM.	26568289
SK-N-AS	Antiproliferative assay		72 hrs		Antiproliferative activity against human SK-N-AS cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.139 μM.	26568289
SK-N-FI	Antiproliferative assay		72 hrs		Antiproliferative activity against human SK-N-FI cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.401 μM.	26568289
NIH/3T3	Antitumor assay	50 mg/kg	10 days		Antitumor activity against mouse NIH/3T3 cells expressing EML4-ALK L1196M mutant xenografted in nude mouse assessed as tumor stasis at 50 mg/kg, po qd administered for 10 days	27131066
NIH/3T3	Antitumor assay	50 mg/kg	10 days		Antitumor activity against mouse NIH/3T3 cells expressing EML4-ALK L1196M mutant xenografted in nude mouse assessed as partial tumor regression at 50 mg/kg, po qd administered for 10 days	27131066
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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular	482.62	Fórmula	C₃₀H₃₄N₄O₂	Almacenamiento (Desde la fecha de recepción)	3 años-20°Cpolvo
Nº CAS	1256580-46-7	Descargar SDF		Almacenamiento de soluciones madre	1 año-80°Cen disolvente 1 mes-20°Cen disolvente
Sinónimos	AF-802, RG-7853,CH5424802			Smiles	CCC1=CC2=C(C=C1N3CCC(CC3)N4CCOCC4)C(C5=C(C2=O)C6=C(N5)C=C(C=C6)C#N)(C)C

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 7 mg/mL (14.5 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:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

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)

Dosis: mg/kg Peso promedio de los animales: g Volumen de dosificación por animal:μL Número de animales:

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	ALK (F1174L) (Cell-free assay) 1 nM ALK (Cell-free assay) 1.9 nM ALK (R1275Q) (Cell-free assay) 3.5 nM
In vitro	The dissociation constant (KD) value of CH5424802 for ALK in an ATP-competitive manner is 2.4 nM. CH5424802 has substantial inhibitory potency against both native ALK and L1196M with K_i of 0.83 nM and 1.56 nM, respectively. CH5424802 prevents autophosphorylation of ALK in NCI-H2228 NSCLC cells expressing EML4-ALK. CH5424802 also suppresses the phosphorylation of STAT3 and AKT, but not of ERK1/2. CH5424802 completely inhibits the phosphorylation of STAT3 at Tyr705. CH5424802 is preferentially efficacious against NCI-H2228 cells expressing EML4-ALK, but not ALK fusion-negative NSCLC cell lines, including HCC827 cells (EGFR exon 19 deletion), A549 cells (KRAS mutant), or NCI-H522 cells (EGFR wild-type, KRAS wild-type, and ALK wild-type) in monolayer culture. CH5424802 elicits an apoptotic marker—caspase-3/7-like activation—in NCI-H2228 spheroid cells. CH5424802 blocks the growth of two lymphoma lines, KARPAS-299 and SR, with NPM-ALK fusion protein but does not influence the growth of an HDLM-2 lymphoma line without ALK fusion. CH5424802 displays high target selectivity and the stronger anti-proliferative activity against KARPAS-299. CH5424802 inhibits KAPRAS-299 with an IC50 of 3 nM, and KDR with IC50 of 1.4 μM. The metabolic stability of CH5424802 is very high.
Ensayo de quinasa	Ensayos inhibitorios de quinasa in vitro
Ensayo de quinasa	La capacidad inhibitoria contra cada quinasa, excepto MEK1 y Raf-1, se evalúa examinando su capacidad para fosforilar varios péptidos sustrato en presencia de CH5424802 utilizando el ensayo de transferencia de energía por resonancia de fluorescencia resuelta en el tiempo (TR-FRET) o el ensayo de polarización de fluorescencia (FP). La actividad inhibitoria contra MEK1 se evalúa mediante análisis cuantitativo de la fosforilación de un péptido sustrato por una proteína ERK2 recombinante en presencia de CH5424802. La actividad inhibitoria contra Raf-1 se evalúa examinando la capacidad de las quinasas para fosforilar MEK1 en presencia de CH5424802.
In vivo	Oral administration of CH5424802 dose-dependently inhibits tumor growth with an ED50 of 0.46 mg/kg and tumor regression. Treatment of 20 mg/kg CH5424802 reveals rapid tumor regression by 168%, the tumor volume in any mouse is <30 mm³ after 11 days of treatment (at day 28), a potent antitumor effect is maintained, and tumor regrowth does not occur throughout the 4-week drug-free period. The half-life and the oral bioavailability of CH5424802 in mice are 8.6 hours and 70.8%, respectively. At a repeated dose of 6 mg/kg, the mean plasma levels reached 1.7, 1.5, and 0.3 nM at 2, 7, and 24 hours post-dose, respectively. Administration of CH5424802 leads to tumor growth prevention and tumor regression. Tumor growth inhibition at 20 mg/kg is 119% for KARPAS-299 and 104% for NB-1 on day 20. CH5424802 inhibits the phosphorylation of STAT3 in a dose-dependent manner (2–20 mg/kg). A partial decrease in AKT phosphorylation is also observed in CH5424802-treated xenograft tumors.
Referencias	[1] https://pubmed.ncbi.nlm.nih.gov/21575866/ [2] https://pubmed.ncbi.nlm.nih.gov/22225917/

Aplicaciones (Applications)

Métodos	Biomarcadores	Imágenes	PMID
Western blot	pALK / ALK / pAKT / AKT / pERK / ERK / pS6 / S6 PARP / cleaved PARP / Akt / caspase 3 / Cleaved caspase 3 pROS1 / ROS1 / pSTAT3 / STAT3 p-EGFR Tyr1068 / EGFR / p-HER3 Tyr1222 / HER3 / p-IGF-1R Tyr1135 / IGF-1R		25228534
Growth inhibition assay	Cell viability		25228534

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
NCT05987956	Not yet recruiting	Non-small Cell Lung Cancer	Han Xu M.D. Ph.D. FAPCR Sponsor-Investigator IRB Chair\|Medicine Invention Design Inc	March 8 2024	Phase 2\|Phase 3
NCT05987644	Recruiting	Lung Cancer\|NSCLC\|Brain Metastases	Joshua Palmer\|Genentech Inc.\|Hoosier Cancer Research Network	March 7 2024	Phase 1\|Phase 2
NCT05710133	Enrolling by invitation	NSCLC	The Netherlands Cancer Institute	February 1 2024	Not Applicable
NCT05770037	Recruiting	Solid Tumor\|Haematological Malignancy\|Malignant Neoplasm\|Lymphoproliferative Disorders\|Neoplasms by Histologic Type\|Neoplasms by Site\|Cancer\|Anaplastic Large Cell Lymphoma\|Lymphoma\|Renal Cell Carcinoma\|Neuroblastoma	Cancer Research UK\|University of Manchester\|University of Birmingham\|Royal Marsden NHS Foundation Trust\|Hoffmann-La Roche	December 18 2023	Phase 2\|Phase 3
NCT05525338	Recruiting	Drug Monitoring\|Carcinoma Non-Small-Cell Lung\|Lung Cancer\|Anaplastic Lymphoma Kinase Gene Mutation\|Anaplastic Lymphoma Kinase Gene Translocation	University Medical Center Groningen\|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)\|Erasmus Medical Center\|Maastricht University Medical Center\|Radboud University Medical Center\|The Netherlands Cancer Institute\|Leiden University Medical Center	March 23 2022	Phase 4
NCT04774718	Recruiting	ALK Fusion-positive Solid or CNS Tumors	Hoffmann-La Roche	September 14 2021	Phase 1\|Phase 2

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