Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
American journal of cancer research	8	8	2018	1541-1550	Am J Cancer Res

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
TQ-B3139	TQ-B3139	10	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TQ-B3139		TQB3139\|TQ B3139\|CT-711\|CT 711\|CT711\|Envonalkib	ALK Inhibitor 32 MET Inhibitor 59	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 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
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 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 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
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