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|Ref Type||Journal Article|
|Authors||Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y|
|Title||CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.|
|Date||2011 May 17|
|Abstract Text||Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, 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, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Alectinib||Alecensa||CH5424802|RO5424802||ALK Inhibitor 23 RET Inhibitor 39||Alecensa (alectinib) is an inhibitor of RET and ALK, including ALK fusions and the gatekeeper mutation, L1196M (PMID: 21575866, PMID: 25349307). Alecensa (alectinib) is FDA-approved for use in patients with ALK-positive (rearrangements and fusions) non-small cell lung cancer (FDA.gov).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK ALK L1196M||Advanced Solid Tumor||conflicting||Alectinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing an EML4-ALK fusion and ALK L1196M in culture and in cell line xenograft models (PMID: 21575866).||21575866|
|EML4 - ALK||lung non-small cell carcinoma||sensitive||Alectinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Alecensa (alectinib) inhibited Alk phosphorylation and growth of a human non-small cell lung cancer cell line harboring EML4-ALK in culture and in cell line xenograft models (PMID: 21575866).||21575866|
|ALK C1156Y||Advanced Solid Tumor||sensitive||Alectinib||Preclinical||Actionable||In a preclinical study, ALK C1156Y was sensitive to Alecensa (alectinib) in an in vitro enzyme assay (PMID: 21575866).||21575866|
|EML4 - ALK ALK C1156Y||Advanced Solid Tumor||sensitive||Alectinib||Preclinical - Cell culture||Actionable||In a preclinical study, transformed human cells expressing EML4-ALK with ALK C1156Y were sensitive to Alecensa (alectinib) in culture (PMID: 21575866).||21575866|