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Description: Alectinib HCl (formerly AF802, CH5424802 or RO5424802; trade name ALECENSA) is a potent, selective, and orally bioavailable inhibitor of ALK (anaplastic lymphoma kinase) tyrosine kinase with IC50 value of 1.9 nM in cell-free assays. Alectinib has potential anticancer activity and was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC).
References: Cancer Cell. 2011 May 17;19(5):679-90; Bioorg Med Chem. 2012 Feb 1;20(3):1271-80.
Related CAS: 1256580-46-7 (free base) 1256589-74-8 (HCl)
InChi Key: GYABBVHSRIHYJR-UHFFFAOYSA-N
InChi Code: InChI=1S/C30H34N4O2.ClH/c1-4-20-16-23-24(17-26(20)34-9-7-21(8-10-34)33-11-13-36-14-12-33)30(2,3)29-27(28(23)35)22-6-5-19(18-31)15-25(22)32-29;/h5-6,15-17,21,32H,4,7-14H2,1-3H3;1H
SMILES: N#CC1=CC2=C(C=C1)C3=C(C(C)(C)C4=CC(N5CCC(N6CCOCC6)CC5)=C(CC)C=C4C3=O)N2.[H]Cl
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: 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. 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.
Kinase Assay: 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 Assay: Cells (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.
Cancer Cell. 2011 May 17;19(5):679-90; Bioorg Med Chem. 2012 Feb 1;20(3):1271-80.
Purity ≥98%
The structure and cytotoxicity of alectinib. Exp Mol Med. 2017 Mar; 49(3): e303.
Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a). Exp Mol Med. 2017 Mar; 49(3): e303.
Effect of alectinib on the intracellular accumulations of DOX and Rho 123 in MDR cells and in their parental sensitive cells. Exp Mol Med. 2017 Mar; 49(3): e303.