生物活性

• 靶点	ALK IC50:0.2nM

• 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. Ceritinib is a selective inhibitor of ALK with IC50 value of 0.2nM (measured by enzymatic kinase activity), and less potent to FLT3, IGF-1R, InsR and STK22D with IC50 values of 60nM, 8nM, 7nM and 23nM, respectively, and showed inhibitory activity on celluar kinase in Ba/F3 cells with IC50 values of 40.7nM, 2.2nM, 410nM and 141.8nM for Tel-ALK, EML4-ALK, Tel-IGF-1R and Tel-Ros, respectively. The cell proliferation study showed that Ceritinib exhibited preferential anti-proliferative activity in Ba/F3 cells expressing NPM-ALK (26nM) and in Karpas299 cells with NPM-ALK fusion (22.8nM)^[1]. As the second generation of ALK inhibitor, Ceritinib can overcome several crizotinib resistant mutations in non–small cell lung cancers, including in two ALK-rearranged lung cancer cell lines H3122 and H2228, ALK-mutant cells, H3122 CR1 (L1196M), MGH021-4 (G1269A) and MGH045 (L1196M) cells, as well as ALK wild-type (WT) crizotinib-resistant MGH051 cells from patient, and lead inhibition on p-ALK, p-AKT, p-ERK,p-S6 and cell proliferation at much lower dose than Crizotinib. Consistent with the in vitro study, ceritinib showed more potent anti-tumor activity at dose (50mg/kg) lower than crizotinib (100mg/kg) in mice bearing crizotinib-resistant tumors harboring EML4–ALK wild-type, I1171T, or C1156Y mutations^[2].
• 作用机制Ceritinib is an ATP-competitive ALK inhibitor.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  Ba/F3 EA C1156Y	-	Growth Inhibition Assay	72 h	IC50=0.026 μM	25727400
  Ba/F3 EA G1202R	-	Growth Inhibition Assay	72 h	IC50=0.467 μM	25727400
  Ba/F3 EA G1269A	-	Growth Inhibition Assay	72 h	IC50=0.033 μM	25727400

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• 动物研究
  剂量	Nude Mice: 25 mg/kg, 50 mg/kg[4] (p.o.) Mice: 5 mg/kg - 25 mg/kg[1] (i.v.), 20 mg/kg[1] (p.o.) Rat: 3 mg/kg - 10 mg/kg[1] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Monkeys[1] Dose 5 mg/kg (i.v.) 20 mg/kg (p.o.) 3 mg/kg (i.v.) 10 mg/kg (p.o.) 5 mg/kg (i.v.) 20 mg/kg (p.o.) 5 mg/kg (i.v.) 60 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. F 95% (p.o.) 66% (p.o.) 119% (p.o.) 56% (p.o.) T1/2 6.2 h (i.v.) 9.1 h (i.v.) 21 h (i.v.) 26 h (i.v.) Tmax 0.03 h (i.v.) 7.0 h (p.o.) 0.03 h (i.v.) 7.0 h (p.o.) 0.03 h (i.v.) 8.0 h (p.o.) 7 h (i.v.) 13 h (p.o.) CL 26.6 ml/min/kg (i.v.) 26.6 ml/min/kg (i.v.) 9.2 ml/min/kg (i.v.) 12.8 ml/min/kg (i.v.) Cmax 1756 nM (i.v.) 696 nM (p.o.) 770 nM (i.v.) 259 nM (p.o.) 2329 nM (i.v.) 1899 nM (p.o.) 2526 nM (i.v.) 169 nM (p.o.) Vss 9.7 L/kg (i.v.) 21.2 L/kg (i.v.) 13.5 L/kg (i.v.) 15 L/kg (i.v.) AUC 5634 hrs·nM (i.v.) 12296 hrs·nM (p.o.) 2779 hrs·nM (i.v.) 6092 hrs·nM (p.o.) 6790 hrs·nM (p.o.) 11305 hrs·nM (i.v.) 763 hrs·nM (p.o.)

• 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
  NCT02645149	Melanoma	Phase 4	Not yet recruiting	August 2021	Australia, New South Wales ... more >> Royal Prince Alfred Hospital Not yet recruiting Camperdown, New South Wales, Australia, 2050 Contact: Maria Gonzalez    612 9911 7200    maria.gonzalez@melanoma.org.au    Principal Investigator: John Thompson          Westmead Hospital Westmead, New South Wales, Australia, 2145 Melanoma Institute Australia Not yet recruiting Wollstonecraft, New South Wales, Australia, 2065 Contact: Maria Gonzalez    +612 9911 7200    maria.gonzalez@melanoma.org.au    Contact: Alex Menzies    +612 9911 7200    info@melanoma.org.au    Sub-Investigator: Georgina Long          Principal Investigator: Alex Menzies Collapse <<
  NCT02551718	Acute Leukemia of Ambiguous Li... more >>neage Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Refractory Adult Acute Lymphoblastic Leukemia Refractory Childhood Acute Lymphoblastic Leukemia Collapse <<	Not Applicable	Recruiting	-	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Pamela S. Becker    206-616-1589    pbecker@u.washington.edu    Principal Investigator: Pamela S. Becker Collapse <<
  NCT03413176	-	-	Completed	-	France ... more >> AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1421, Pharmacovigilance Unit, INSERM. Paris, France, 75013 Collapse <<

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• 参考文献

• [1] Marsilje TH, Pei W, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013;56(14):5675-90.

  [2] Friboulet L, Li N, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662-673.

  [3] Burns MW, Kim ES. Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer. Lung Cancer (Auckl). 2015.

  [4] van Erp AEM, Hillebrandt-Roeffen MHS, et al. Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib. Target Oncol. 2017 Dec;12(6):815-826.