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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4 Customer Reviews

  • Immunoblot analysis of full-length DCTN1-ALK proteins. An expression vector encoding DCTN1-ALK cDNA was introduced into H1299 lung cancer cells, which do not express endogenous ALK. The transfectants were then exposed to crizotinib and alectinib. Levels of phosphorylation at tyrosine 1604 were determined 24 hours after treatment with 0, 0.2, 1.0, or 5.0 μM of each drug.

    Oncologist, 2017, 22(2):158-164. Alectinib (CH5424802) purchased from Selleck.

    Sensitivity of the H3122 cell line to ALK inhibitors (crizotinib and alectinib). To examine the sensitivity of ALK inhibitors, used an MTT assay. The experiment was performed in triplicate. (A) Growth inhibitory effect of crizotinib. The H3122 cell line was sensitive to crizotinib under a normoxic state, compared with a hypoxic state. The graphs, mean of independent triplicate experiments; error bars, SD. (B) IC50 of ALK inhibitors. The IC50 values of both inhibitors in the H3122 cell lines were significantly higher under hypoxia than under normoxia (crizotinib, *P=0.028 and alectinib, *P=0.0035). *P<0.05.

    Int J Oncol 2014 45(4), 1430-6. Alectinib (CH5424802) purchased from Selleck.

  • Western blotting data of NPM/ALK-transformed BaF3 cells, both wild-type and L1196M-mutant, treated with CH5424802 for 4 hours. The blot shows phospho-ALK signal (Y1604), as an indicator of NPM/ALK activation.

    Prof. Gambacorti from Università degli Studi di Milano Bicocc. Alectinib (CH5424802) purchased from Selleck.

    Cell growth data, performed by tritiated thymidine uptake assay, using NPM/ALK wild-type -transformed BaF3 cells.CH5424802 demonstrated a very good ability to block NPM/ALK-transformed BaF3 cells proliferation with an IC50 of 3 nM.

    Prof. Gambacorti from Università degli Studi di Milano Bicocc. Alectinib (CH5424802) purchased from Selleck.

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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 NFLSfpVMcW6jc3WgZZN{[Xl? M4\1Xp4yKM7:TR?= NGrGd5hxemW4ZX70d{BifXSxcHjvd5Bpd3K7bHH0bY9vKG:oIFHMTy=> NYHRZZJjOjF3N{W4OlY>
KARPAS-299 M2SyOWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NVjIVFVjhjFyIN88US=> MmX2TWM2OD1|IH7N M2DsS|IyPTd3OE[2
SR M3PofGdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MW\+NVAh|ryP NX7q[5IxUUN3ME22Mlkhdk1? NUHJe41COjF3N{W4OlY>
HDLM-2 MVjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MV7+NVAh|ryP NIDI[45KSzVyPkGwMFAxOCCwTR?= MlzTNlE2PzV6Nk[=
NB-1 MYnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? Mni0glExKM7:TR?= NXTsd|l4UUN3ME20MlUhdk1? MoLhNlE2PzV6Nk[=
KELLY M4qzd2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MoLNglExKM7:TR?= MlT6TWM2OD14MjDuUS=> NF7uZZYzOTV5NUi2Oi=>
SK-N-FI M1PKZmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MoDvglExKM7:TR?= M3zUVGlEPTB-MUCsNFAxKG6P NH\1PYwzOTV5NUi2Oi=>
NCI-H2228 NEHKSIFIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M4rINJ4yOCEQvF2= NVjVW2pvUUN3ME21N{BvVQ>? NGT1cpczOTV5NUi2Oi=>
Calu-3 NFrzfJRIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NGHtUlB,OTBizszN MYTJR|UxRT5zMDywNFAhdk1? MViyNVU4PTh4Nh?=
PC-1 MWnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MmL6glExKM7:TR?= Mor1TWM2OD5zMDywNFAhdk1? NFLIXZEzOTV5NUi2Oi=>
NCI-H23 NI[3TnVIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NGGzSXV,OTBizszN M3vydWlEPTB;M{[wNEBvVQ>? Ml:2NlE2PzV6Nk[=
Calu-1 Mnn5S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NYSzdpM5hjFyIN88US=> NV34UVhrUUN3ME6xNEwxODBibl2= MlfaNlE2PzV6Nk[=
NCI-H2009 MmHHS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NVnLTnhLhjFyIN88US=> MkTSTWM2OD5zMDywNFAhdk1? NHzk[2EzOTV5NUi2Oi=>
NCI-H1993 MXTHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NETZRYJ,OTBizszN M4HkTGlEPTB-MUCsNFAxKG6P NFK2eJAzOTV5NUi2Oi=>
MKN-45 NX\hRpVmT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NUW3Z45zhjFyIN88US=> MmLPTWM2OD5zMDywNFAhdk1? NHr1bmozOTV5NUi2Oi=>
SNU-5 M1rN[Gdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MX\+NVAh|ryP NFzyXlVKSzVyPUG4NFAhdk1? NIn4V5YzOTV5NUi2Oi=>
KATO-III NHHpOXNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NEfBZnV,OTBizszN NYXvNYJ1UUN3ME23PVAxKG6P NYrqO4JSOjF3N{W4OlY>
SK-BR-3 MVPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NWrwXXlwhjFyIN88US=> NW[xc|M{UUN3ME6xNEwxODBibl2= NWXTVldzOjF3N{W4OlY>
BT-483 MWrHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4HqXp4yOCEQvF2= NHjFfYNKSzVyPkGwMFAxOCCwTR?= M3vIblIyPTd3OE[2
PC-3 MkC0S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NWXTUIZrhjFyIN88US=> MYjJR|UxRjFyLECwNEBvVQ>? NF3ueoIzOTV5NUi2Oi=>
22Rv1 NGjzdJJIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MYD+NVAh|ryP M33jXmlEPTB-MUCsNFAxKG6P NUT5PJB5OjF3N{W4OlY>
U-87 MG MlPNS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NXvtco1qhjFyIN88US=> NHr5b2hKSzVyPkGwMFAxOCCwTR?= NVX5do9JOjF3N{W4OlY>
H3122 MVnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NFHiOJR,OTBizszN Mln6TWM2OD1|MzDuUS=> MXSyOVA6PjRyMB?=
LC-2/ad M3Tz[2Fxd3C2b4Ppd{Bie3OjeR?= NXvMOlB[hjFizszN Mn[2SG1UVw>? NVTUTY1YcW6mdXPld{BieG:ydH;zbZM> NXXBSVJ6OjV|NEmzNFc>
LC-2/ad M1jHVGZ2dmO2aX;uJIF{e2G7 NHzUfYN,OSEQvF2= M2LHT2ROW09? MnGzbY5pcWKrdIOgeIhmKE2DUFugd4lodmGuaX7nJJBifGi5YYm= NHPCOnczPTN2OUOwOy=>
Ba/F3 NGTrc2tHfW6ldHnvckBie3OjeR?= NUG4dIJLhjFizszN M2nIV2ROW09? NWT1[I1Fe3WycILld5NmeyCyaH;zdIhwenmuYYTpc44hd2ZiRWLLJIFv\CCrbnPy[YF{\XNidHjlJIFjfW6mYX7j[UBw\iCESV2= M1ziXlI2OzR7M{C3
SNU-2535 NYH0ZZJ4T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXj+NVAh|ryP Ml3jTWM2OD1|Mz6xJI5O NVnyTpZnOjZ6NEm2N|c>
SNU-2535 MUnLbY5ie2ViYYPzZZk> NEfUd4R,OSEQvF2= M4rue4lvcGmkaYTzJJRp\SCyaH;zdIhwenmuYYTpc44hd2ZiQVzLJIFv\CCrdIOg[I94dnO2cnXhcUBud2ynY4Xs[ZMhTVKNMT:yJIFv\CCDS2S= NFzIR|kzPjh2OU[zOy=>

... Click to View More Cell Line Experimental Data

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]
+ Expand

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]
+ Expand
  • 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]
+ Expand
  • 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 individually and in order:
30% PEG400+0.5% Tween80+5% propylene glycol
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
Synonyms AF-802,RG-7853

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02314481 Not yet recruiting Non-small Cell Lung Cancer University College, London|Hoffmann-La Roche January 2017 Phase 2
NCT02838420 Recruiting Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Hoffmann-La Roche August 2016 Phase 3
NCT02621047 Recruiting Hepatic Impairment Hoffmann-La Roche December 2015 Phase 1
NCT02604342 Recruiting Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Hoffmann-La Roche November 2015 Phase 3
NCT02521051 Recruiting Non-Small Cell Lung Cancer (NSCLC) Massachusetts General Hospital|Genentech, Inc. October 2015 Phase 1|Phase 2
NCT02271139 Completed Non-Small Cell Lung Cancer Genentech, Inc. December 2014 --

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID