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Ref Type Journal Article
PMID (30210922)
Authors Wang L, Gao M, Tong M, Xie C, He Y, Fu L, Li Y, Fu H, Lou L
Title Pharmacologic characterization of CT-711, a novel dual inhibitor of ALK and c-Met.
Journal American journal of cancer research
Vol 8
Issue 8
Date 2018
URL
Abstract Text Anaplastic lymphoma kinase (ALK) is a validated molecular target for patients harboring ALK rearrangement, which triggers the development of ALK inhibitors. However, the activation of mesenchymal-epithelial transition factor (c-Met) has emerged as a common cause of acquired resistance induced by selective ALK inhibitors. Herein, we report the first preclinical characterization of CT-711, a novel dual inhibitor of ALK and c-Met. CT-711 demonstrates potent inhibitory activity against ALK kinase activity. Moreover, CT-711 profoundly inhibits ALK signal transduction and thereby induces G1 phase arrest and apoptosis, and results in remarkable anti-proliferative activity against ALK-driven cancer cells. Furthermore, CT-711 effectively inhibits c-Met kinase activity and potently overcomes the resistance mediated by c-Met activation. When orally administered to nude mice bearing xenografts, CT-711 exhibits favorable pharmacokinetic properties and robust antitumor activity. It is noteworthy that CT-711 is superior to crizotinib, the first-in-class ALK inhibitor, in the treatment of ALK-driven cancers in various models. The results of the current study provide a solid foundation for the clinical investigation of CT-711 in patients with tumors harboring ALK rearrangement.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
TQ-B3139 TQB3139|TQ B3139|CT-711|CT 711|CT711 ALK Inhibitor 29 MET Inhibitor 56 TQ-B3139 (CT-711) inhibits MET and ALK, with activity against ALK mutations, potentially resulting in decreased Alk signaling, induction of cell cycle arrest and apoptosis in tumor cells, and reduced proliferation and tumor growth (PMID: 30210922).
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 C1156Y Advanced Solid Tumor sensitive TQ-B3139 Preclinical - Cell line xenograft Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of cells expressing EML4-ALK with ALK C1156Y in culture and inhibited tumor growth in a cell line xenograft model (PMID: 30210922). 30210922
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive TQ-B3139 Preclinical - Cell line xenograft Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of cells expressing EML4-ALK with ALK L1196M in culture and inhibited tumor growth in a cell line xenograft model (PMID: 30210922). 30210922
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive TQ-B3139 Preclinical - Cell culture Actionable In a preclinical study, TQ-B3139 (CT-117) inhibited proliferation of a cells expressing EML4-ALK with ALK L1152R in culture (PMID: 30210922). 30210922
ALK F1174L neuroblastoma sensitive TQ-B3139 Preclinical - Cell line xenograft Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of a neuroblastoma cell line harboring ALK F1174L in culture and inhibited tumor growth in a cell line xenograft model (PMID: 30210922). 30210922
EML4 - ALK Advanced Solid Tumor sensitive TQ-B3139 Preclinical - Cell line xenograft Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of cells expressing EML4-ALK in culture and inhibited tumor growth in a cell line xenograft model (PMID: 30210922). 30210922
EML4 - ALK lung non-small cell carcinoma sensitive TQ-B3139 Preclinical - Cell line xenograft Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited Alk signaling and proliferation and induced cell cycle arrest and apoptosis in non-small cell lung cancer cell lines harboring EML4-ALK in culture and induced tumor regression in cell line xenograft models (PMID: 30210922). 30210922
EML4 - ALK ALK R1275Q Advanced Solid Tumor sensitive TQ-B3139 Preclinical - Cell culture Actionable In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of cells expressing EML4-ALK with ALK R1275Q in culture (PMID: 30210922). 30210922