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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3 Customer Reviews

  • 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.

Purity & Quality Control

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

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)
INSR [1]
(Cell-free assay)
KDR [1]
(Cell-free assay)
1 nM 1.9 nM 3.5 nM 550 nM 1.4 μM
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 MnfTT4lv[XOnIHHzd4F6 NVfkWVN6hjFizszN M1nHO5Bz\X[nboTzJIF2fG:yaH;zdIhwenmuYYTpc44hd2ZiQVzL NXHQZXhzOjF3N{W4OlY>
KARPAS-299 NGe5[HpIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MkT1glExKM7:TR?= MkDnTWM2OD1|IH7N NFXrZXgzOTV5NUi2Oi=>
SR MY\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MmPBglExKM7:TR?= MWfJR|UxRTZwOTDuUS=> Ml;5NlE2PzV6Nk[=
HDLM-2 NIW5cJNIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MmLNglExKM7:TR?= NWnBfGt4UUN3ME6xNEwxODBibl2= MlTsNlE2PzV6Nk[=
NB-1 MXLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M4rsPZ4yOCEQvF2= M4HlfmlEPTB;ND61JI5O NYrTTYtiOjF3N{W4OlY>
KELLY MYDHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MV7+NVAh|ryP NGXle2ZKSzVyPU[yJI5O MV2yNVU4PTh4Nh?=
SK-N-FI NHi5OYZIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M4PGR54yOCEQvF2= Mlq0TWM2OD5zMDywNFAhdk1? M2jlXlIyPTd3OE[2
NCI-H2228 M3m4S2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NUnvU3I5hjFyIN88US=> M4XWdGlEPTB;NUOgcm0> M4Kx[|IyPTd3OE[2
Calu-3 M1fPcWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NUPsRpJrhjFyIN88US=> Mnn0TWM2OD1-MUCsNFAxKG6P NV62[G9oOjF3N{W4OlY>
PC-1 M{j5Z2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 MV;+NVAh|ryP NXrqUo9[UUN3ME6xNEwxODBibl2= M{K1clIyPTd3OE[2
NCI-H23 NYLvcFBpT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MVT+NVAh|ryP MnvWTWM2OD1|NkCwJI5O MYiyNVU4PTh4Nh?=
Calu-1 MY\Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NWi3V4lXhjFyIN88US=> MVLJR|UxRjFyLECwNEBvVQ>? NWXQ[pB4OjF3N{W4OlY>
NCI-H2009 M2jRe2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NFTUeXR,OTBizszN NUPtR4pyUUN3ME6xNEwxODBibl2= M1fLdVIyPTd3OE[2
NCI-H1993 NYTHeWtGT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= M3Hpc54yOCEQvF2= MkHPTWM2OD5zMDywNFAhdk1? Mn72NlE2PzV6Nk[=
MKN-45 MlG2S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MYD+NVAh|ryP MlL0TWM2OD5zMDywNFAhdk1? MnjYNlE2PzV6Nk[=
SNU-5 NWT5OW9uT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NEnHOXp,OTBizszN MlfCTWM2OD1zOECwJI5O NW\6NVlqOjF3N{W4OlY>
KATO-III NEDCZnpIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= MYn+NVAh|ryP NFfJcYdKSzVyPUe5NFAhdk1? MYCyNVU4PTh4Nh?=
SK-BR-3 NXfRNIJYT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= NWHTbpZbhjFyIN88US=> MX7JR|UxRjFyLECwNEBvVQ>? MWqyNVU4PTh4Nh?=
BT-483 MXzHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MlixglExKM7:TR?= Mnn0TWM2OD5zMDywNFAhdk1? MlPyNlE2PzV6Nk[=
PC-3 MVfHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? M2DQVZ4yOCEQvF2= MmK5TWM2OD5zMDywNFAhdk1? NHnTfGczOTV5NUi2Oi=>
22Rv1 NXHiSm1YT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm= MXX+NVAh|ryP M17oUmlEPTB-MUCsNFAxKG6P MVSyNVU4PTh4Nh?=
U-87 MG Mn7NS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MXz+NVAh|ryP NEX1d3lKSzVyPkGwMFAxOCCwTR?= NVrLNnF6OjF3N{W4OlY>
H3122 NFHifXlIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NHPCdJN,OTBizszN NEPxRmRKSzVyPUOzJI5O M3LGNlI2ODl4NECw
LC-2/ad M2nV[2Fxd3C2b4Ppd{Bie3OjeR?= M4PaZ54yKM7:TR?= MW\EUXNQ NHK1VWRqdmS3Y3XzJIFxd3C2b4Ppdy=> NGjwdmczPTN2OUOwOy=>
LC-2/ad NHXrSo1HfW6ldHnvckBie3OjeR?= NWLqb443hjFizszN M1fhUWROW09? NVHjfpNycW6qaXLpeJMhfGinIF3BVGshe2mpbnHsbY5oKHCjdHj3ZZk> NGTF[o8zPTN2OUOwOy=>
Ba/F3 MW\GeY5kfGmxbjDhd5NigQ>? MVT+NUDPxE1? MWXEUXNQ NUH5XWZJe3WycILld5NmeyCyaH;zdIhwenmuYYTpc44hd2ZiRWLLJIFv\CCrbnPy[YF{\XNidHjlJIFjfW6mYX7j[UBw\iCESV2= NXLYZohjOjV|NEmzNFc>
SNU-2535 Mm[4S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? MkPDglExKM7:TR?= MkHFTWM2OD1|Mz6xJI5O M3jXNlI3QDR7NkO3
SNU-2535 MnT5T4lv[XOnIHHzd4F6 NXX2VpdzhjFizszN NY\FeXpmcW6qaXLpeJMhfGinIIDoc5NxcG:{eXzheIlwdiCxZjDBUGsh[W6mIHn0d{Bld3ewc4Ty[YFuKG2xbHXjeYxmeyCHUluxM|Ih[W6mIFHLWC=> NFzVUI0zPjh2OU[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
+ 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
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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
+ 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 (1.03 mM) warming
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* 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 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 July 2016 Phase 3
NCT02621047 Recruiting Hepatic Impairment Hoffmann-La Roche November 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 Active, not recruiting Non-Small Cell Lung Cancer Genentech, Inc. December 2014 Phase 3

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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