Alectinib (CH5424802)

Catalog No.S2762 Synonyms: AF-802,RG-7853

Alectinib (CH5424802) Chemical Structure

Molecular Weight(MW): 482.62

Alectinib (CH5424802) is a potent ALK inhibitor with IC50 of 1.9 nM in cell-free assays, sensitive to L1196M mutation and higher selectivity for ALK than PF-02341066, NVP-TAE684 and PHA-E429.

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Cited by 22 Publications

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Biological Activity

Description Alectinib (CH5424802) is a potent ALK inhibitor with IC50 of 1.9 nM in cell-free assays, sensitive to L1196M mutation and higher selectivity for ALK than PF-02341066, NVP-TAE684 and PHA-E429.
Targets
ALK (F1174L) [1]
(Cell-free assay)
ALK [1]
(Cell-free assay)
ALK (R1275Q) [1]
(Cell-free assay)
1 nM 1.9 nM 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 Ki 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. [1] 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.[2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
NCI-H2228 NITESHJMcW6jc3WgZZN{[Xl? NX\wVXpOhjFizszN NW\RXVY4eHKndnXueJMh[XW2b4Doc5NxcG:{eXzheIlwdiCxZjDBUGs> NEHYepMzOTV5NUi2Oi=>
KARPAS-299 NYO1e2VCT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MUf+NVAh|ryP NX\D[HlyUUN3ME2zJI5O Moi4NlE2PzV6Nk[=
SR M3XzN2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NUHCVnpLhjFyIN88US=> Mnv1TWM2OD14Lkmgcm0> NHP0ZpUzOTV5NUi2Oi=>
HDLM-2 MWDHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NFvjZod,OTBizszN NGLlNolKSzVyPkGwMFAxOCCwTR?= NIHGPIUzOTV5NUi2Oi=>
NB-1 NY[1RXRqT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NVq1OVE1hjFyIN88US=> NWTVcJU3UUN3ME20MlUhdk1? NYfZXnpYOjF3N{W4OlY>
KELLY Mmf0S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NGrlNoF,OTBizszN MoTlTWM2OD14MjDuUS=> MkLmNlE2PzV6Nk[=
SK-N-FI MV7Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NFnTemJ,OTBizszN MmfzTWM2OD5zMDywNFAhdk1? NXvhOpptOjF3N{W4OlY>
NCI-H2228 NXuzfG5KT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= Mm\5glExKM7:TR?= MnTLTWM2OD13MzDuUS=> NUn6UXRrOjF3N{W4OlY>
Calu-3 NYXkPGl7T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MX3+NVAh|ryP NWS3UI12UUN3ME2+NVAtODByIH7N NXvTTXVQOjF3N{W4OlY>
PC-1 NHzSfIpIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MkXWglExKM7:TR?= MWnJR|UxRjFyLECwNEBvVQ>? NH7lem4zOTV5NUi2Oi=>
NCI-H23 MmfyS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NULK[4dthjFyIN88US=> M2PYPGlEPTB;M{[wNEBvVQ>? NHLlWmwzOTV5NUi2Oi=>
Calu-1 NXvDdmFCT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MWP+NVAh|ryP NVn4WYxOUUN3ME6xNEwxODBibl2= NHvKfVAzOTV5NUi2Oi=>
NCI-H2009 M17rXmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MlG0glExKM7:TR?= Ml3GTWM2OD5zMDywNFAhdk1? NV\YN41zOjF3N{W4OlY>
NCI-H1993 NW\ve|RTT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MoXiglExKM7:TR?= M2HWPGlEPTB-MUCsNFAxKG6P NGDRbHkzOTV5NUi2Oi=>
MKN-45 NH;NNIxIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M{Tnc54yOCEQvF2= NH7CVIpKSzVyPkGwMFAxOCCwTR?= NYD0N|d2OjF3N{W4OlY>
SNU-5 MmnpS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MWf+NVAh|ryP MWDJR|UxRTF6MECgcm0> NH7wOFczOTV5NUi2Oi=>
KATO-III M{LvNGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NXGxZnl4hjFyIN88US=> MYnJR|UxRTd7MECgcm0> NHjCR4UzOTV5NUi2Oi=>
SK-BR-3 M3TmSGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 M3ezRZ4yOCEQvF2= MWjJR|UxRjFyLECwNEBvVQ>? M2jFdVIyPTd3OE[2
BT-483 MX;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NV23bYxWhjFyIN88US=> NYDIPZZnUUN3ME6xNEwxODBibl2= M2HuR|IyPTd3OE[2
PC-3 MW\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NHvVWYJ,OTBizszN M3\Kd2lEPTB-MUCsNFAxKG6P MV:yNVU4PTh4Nh?=
22Rv1 MXTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M{PZUp4yOCEQvF2= M4LyOmlEPTB-MUCsNFAxKG6P NGHPOogzOTV5NUi2Oi=>
U-87 MG NHjVU|FIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MWT+NVAh|ryP NXTTcHlOUUN3ME6xNEwxODBibl2= M4D0cFIyPTd3OE[2
H3122 M4rHeGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NGG0[Yd,OTBizszN Mln5TWM2OD1|MzDuUS=> MXqyOVA6PjRyMB?=
LC-2/ad NGHVOGVCeG:ydH;zbZMh[XO|YYm= M2HXSJ4yKM7:TR?= M1;2NWROW09? MmG3bY5lfWOnczDhdI9xfG:|aYO= NGTCcm4zPTN2OUOwOy=>
LC-2/ad NEf4WXJHfW6ldHnvckBie3OjeR?= MUT+NUDPxE1? NGLZT3JFVVOR NHr3T|dqdmirYnn0d{B1cGViTVHQT{B{cWewYXzpcocheGG2aIfhfS=> MlztNlU{PDl|MEe=
Ba/F3 MYXGeY5kfGmxbjDhd5NigQ>? MnLwglEh|ryP MnXBSG1UVw>? MXnzeZBxemW|c3XzJJBpd3OyaH;yfYxifGmxbjDv[kBGWktiYX7kJIlv[3KnYYPld{B1cGViYXL1coRidmOnIH;mJGJKVQ>? NV3HPWVjOjV|NEmzNFc>
SNU-2535 MVrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NEPiVph,OTBizszN MX7JR|UxRTN|LkGgcm0> NGW2T4gzPjh2OU[zOy=>
SNU-2535 NXvNTVRjU2mwYYPlJIF{e2G7 MW\+NUDPxE1? MmO3bY5pcWKrdIOgeIhmKHCqb4PwbI9zgWyjdHnvckBw\iCDTFugZY5lKGm2czDkc5dve3S{ZXHtJI1wdGWldXzld{BGWktzL{KgZY5lKEGNVB?= NFzJVoYzPjh2OU[zOy=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
pALK / ALK / pAKT / AKT / pERK / ERK / pS6 / S6 ; 

PubMed: 25228534     


Parental H3122 and CHR-A1 cells were treated with alectinib at the indicated concentrations for 6 hrs. Cell extracts were immunoblotted to detect the indicated proteins.

PARP / cleaved PARP / Akt / caspase 3 / Cleaved caspase 3; 

PubMed: 28455243     


Alectinib inhibits PI3K/Akt/mTOR signaling and induces apoptosis in NB cells. NB-19, Kelly, IMR-32, SH-SY5Y, SK-N-AS and LA-N-6 cells were treated with 10 μM alectinib for various time points as indicated. The anti-β-Actin antibody was used as a loading c䲧疝Ỵ疞㧀疜膉痘 瘿⟸෕ᾰƌ

pROS1 / ROS1 / pSTAT3 / STAT3; 

PubMed: 25351743     


Inhibition of phospho-ROS1 by various ALK inhibitors in Ba/F3 models. CD74-ROS1 expressing Ba/F3 cells were exposed to increasing concentrations of crizotinib, ceritinib, AP26113, or ASP3026 for 3 h. Cell lysates were immunoblotted to detect the indicated䲧疝Ỵ疞㧀

p-EGFR Tyr1068 / EGFR / p-HER3 Tyr1222 / HER3 / p-IGF-1R Tyr1135 / IGF-1R; 

PubMed: 26992917     


Cells were treated with indicated drugs for 1 hour; immunoblotting for RTKs in both resistant cell lines showed upregulation of phosphor-EGFR and phosphor-HER3 when compared with parental cells.

25228534 28455243 25351743 26992917
Growth inhibition assay
Cell viability ; 

PubMed: 25228534     


(A) Cells were seeded in 96-well black plates and treated with increasing concentrations of alectinib for 72 hrs. Cell survival was analyzed using the CellTiter-Glo assay. While H3122 cells showed high sensitivity to alectinib (red line), H3122 CHR-A1 cel䲧疝Ỵ疞㧀疜膉痘 瘿�෋ᾰƌ෋à 㺣痖帉痖Ѐ瑖堘𢡄빢᎒෋à鑸᎒彿堙奋堙巫堙᎒ﻺ᎒彿堙ﻮ᎒塚堙ﻺ᎒ꍈ堞빢᎒學堙漸堞圔堙빢᎒圞堙圭堙𢡄玚Wᾰƌ ᾰƌ戤瘯Ɖ⟸෕䐺痖暼瘿⟸෕ᾰƌ

25228534
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. [1]

Protocol

Kinase Assay:[1]
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Kinase inhibitory assays in Vitro:

The inhibitory ability against each kinase except for MEK1 and Raf-1 is evaluated by examining their ability to phosphorylate various substrate peptides in the presence of CH5424802 using time-resolved fluorescence resonance energy transfer (TR-FRET) assay or fluorescence polarization (FP) assay. The inhibitory activity against MEK1 is evaluated by quantitative analysis of the phosphorylation of a substrate peptide by a recombinant ERK2 protein in the presence of CH5424802. The inhibitory activity against Raf-1 is evaluated by examining the ability of the kinases to phosphorylate MEK1 in the presence of CH5424802.
Cell Research:[1]
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  • Cell lines: NSCLC, A549 and HCC827 cell lines
  • Concentrations: 0-1 μM
  • Incubation Time: 5 days
  • Method: Cells including NSCLC, A549 and HCC827 are seeded in 96-well plates overnight and incubated with various concentrations of CH5424802 for the indicated time. For spheroid cell growth inhibition assay, cells are seeded on spheroid plates, incubated overnight, and then treated with compound for the indicated times. The viable cells are measured by the Luminescent Cell Viability Assay. Caspase-3/7 assay is evaluated using the Caspase-Glo 3/7 Assay Kit.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: SCID or nude mice bearing NCI-H2228
  • Formulation: 0.02 N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG400, and 15% HPCD (2-hydroxypropyl-β-cyclodextrin)
  • Dosages: 20 mg/kg
  • Administration: Oral administration
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 0.5 mg/mL warmed (1.03 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing.
30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 482.62
Formula

C30H34N4O2

CAS No. 1256580-46-7
Storage powder
in solvent
Synonyms AF-802,RG-7853

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04111705 Not yet recruiting Drug: Lorlatinib Non Small Cell Lung Cancer Metastatic Intergroupe Francophone de Cancerologie Thoracique October 2019 Phase 2
NCT03445000 Recruiting Drug: Alectinib Non-small Cell Lung Cancer|Non-small Cell Lung Cancer Metastatic|Non-small Cell Lung Cancer Recurrent European Thoracic Oncology Platform|Hoffmann-La Roche November 6 2018 Phase 2
NCT03131206 Active not recruiting Drug: Alectinib ALK-positive Non-small Cell Lung Cancer (NSCLC)|RET-positive Non-small Cell Lung Cancer (NSCLC)|RET-positive Thyroid Cancer Dana-Farber Cancer Institute|Genentech Inc. June 19 2017 Phase 1|Phase 2
NCT02838420 Active not recruiting Drug: Alectinib|Drug: Crizotinib Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Hoffmann-La Roche August 3 2016 Phase 3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID