CH5424802 (AF802) is a potent, selective, and orally available ALK inhibitor. Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers. CH5424802 (AF802) showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors. CH5424802 also blocked EML4-ALK L1196M-driven cell growth.
|Cell lines||KARPAS-299, SR, HDLM-2, NB-1, NCI-H2228, MKN-45, SK-BR-3 cells|
|Preparation method||Cell growth inhibition and caspase-3/7 assay
Cells were incubated with various concentrations of compound for the indicated time. The viable cells were measured by Cell Counting Kit-8 assay (Dojindo Laboratories) or CellTiter-Glo luminescent cell viability assay (Promega). Caspase-3/7 assay was evaluated using the Caspase-Glo 3/7 Assay Kit (Promega).
|Incubation time||96 h|
|Animal models||SCID mice|
|Dosages||6, 20 and 60mg/kg for 7 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Cancer Cell (2011). Figure 5. CH5424802|
|Method||Cell Viability Assay|
|Cell Lines||NSCLC Cell Lines|
|Incubation Time||5 days|
|Results||CH5424802 was 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 NCIH522 cells (EGFR wild-type, KRAS wild-type, and ALK wildtype) in monolayer culture|
Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802).
Kinoshita K, et al. Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. PMID: 22225917.
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Sakamoto H, et al. Cancer Cell. 2011 May 17;19(5):679-90. PMID: 21575866.
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