生物活性

• 靶点	ALK IC50:1.9nM

• 描述ALK (anaplastic lymphoma kinase) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification or point mutation. Alectinib is a potent and selective ALK inhibitor with IC50 value of 1.9nM (measured by enzyme activity). Alectinib 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. Consistent with that, Alectinib can prevent autophosphorylation of ALK and thus resulted in substantial suppression of phosphorylation of STAT3 and AKT, but not of ERK1/2, in NCI-H2228 NSCLC cells expressing EML4-ALK, but not in ALK fusion-negative A549 cells. The potent inhibition of ALK kinase activity by Alectinib can also be observed in vivo. Oral administration of Alectinib caused dose-dependent decrease of pSTAT3-Tyr705 and pAKT-Ser473 in tumors from mice bearing NCI-H2228 cells at dose < 20mg/kg, with a significant decrease in the expression of STAT3 target genes, such as BCL3, NNMT, SOCS3 and BCL2L1, at dose of 6mg/kg. Administered CH5424802 orally once daily for 11 days at dose 2, 6 and 20mg/kg inhibited tumor growth dose-dependently, with decreased pALK-Tyr1604, in mice bearing NCI-H2228 but not A549. The maximum efficacy can be observed at dose of 60mg/kg for 3 weeks and a prolonged effect with no regrowth of tumor for 4 weeks in this model. Therapeutic efficacy of Alectinib on tumor regression can also be observed in models generated by implantation of KARPAS-299 ALCL cells and NB-1 neuroblastoma cells^[1].
• 作用机制Alectinib acts in an ATP-competitive manner and blocks the L1196M gatekeeper mutation of ALK.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22Rv1	~10 μM	Growth inhibitory assay	-	IC50>10,000 nM	21575866
  Ba/F3	~1 μM	Function assay	-	suppresses phosphorylation of ERK and increases the abundance of BIM	25349307
  BT-483	~10 μM	Growth inhibitory assay	-	IC50>10,000 nM	21575866

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• 动物研究
  剂量	Mice: min = 2 mg/kg, max = 20 mg/kg[2] (p.o.); 25 mg/kg[3] (i.p.)
  给药途径	p.o., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03498521	Cancer of Unknown Primary Site	Phase 2	Recruiting	April 16, 2022	-
  NCT01634763	Tumors Characterized by Geneti... more >>c Alterations in Anaplastic Lymphoma Kinase (ALK) Collapse <<	Phase 1	Completed	-	Japan ... more >> Novartis Investigative Site Sunto-gun, Shizuoka, Japan, 411-8777 Novartis Investigative Site Koto, Tokyo, Japan, 135-8550 Novartis Investigative Site Fukuoka, Japan, 811-1395 Collapse <<
  NCT03158389	Glioblastoma, Adult	Phase 1 Phase 2	Recruiting	September 30, 2024	Germany ... more >> Charité Berlin, Neurosurgery Not yet recruiting Berlin, Germany Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic Not yet recruiting Bochum, Germany University Hospital Bonn, Neurology Clinic Not yet recruiting Bonn, Germany University Hospital Cologne, Neurosurgery Not yet recruiting Cologne, Germany University Hospital Dresden, Neurosurgery Not yet recruiting Dresden, Germany University Hospital Essen, Neurology Clinic Not yet recruiting Essen, Germany University Hospital Frankfurt, Neurooncology Not yet recruiting Frankfurt am Main, Germany University Hospital Heidelberg, Neurology Clinic Recruiting Heidelberg, Germany University Hospital Saarland, Neurosurgery Not yet recruiting Homburg, Germany University Hospital Mainz, Neurosurgery Not yet recruiting Mainz, Germany University Hospital Mannheim, Neurology Clinic Not yet recruiting Mannheim, Germany University Hospital Regensburg, Neurology Clinic Not yet recruiting Regensburg, Germany University Hospital Tuebingen, Neurooncology Not yet recruiting Tübingen, Germany Collapse <<

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