生物活性

• 靶点	ALK IC50:100nM

• 描述ALK, known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), is an enzyme that in humans is encoded by the ALK gene. It plays a pivotal role in cellular communication and in the normal development and function of the nervous system. In vitro, Brigatinib is a ALK tyrosine kinase receptor inhibitor with IC₅₀ values of 0.62nM in H3122 human non-small-cell lung cancer cells (measured by ATP assay) ^[6], 10 and 24 nM in Ba/F3 cells (expressing either native or mutant EML4-ALK , respectively) ^[6], 2.00 - 10.2 nM in PC12 rat pheochromocytoma cells with different ALK mutations ^[7]. Brigatinib was highly active against both sensitive and resistant H3122 cells, decreasing cell growth, suppressing ALK phosphorylation, and inducing apoptosis in 300 nM. In PC12 cells, Brigatinib inhibited and abolished ALK phosphorylation in a dose-dependent manner at concentration ranging from 50 to150 nM, suggesting its inhibition on ALK activity and abrogating proliferation of ALK addicted neuroblastoma cell lines; it also effectively abrogated neurite outgrowth of all tested ALK mutants at both 15 and 30 nM, including ALK-G1269A, ALK-R1275 and ALK-R1192P, suggesting its constitutive inhibition on active ALK mutants and neurite outgrowth. In vivo,dose-dependent antitumor activities were discovered both in a Karpass-299 xenograft mouse model( expressing the NPM−ALK fusion) orally administered with Brigatinib (10mg/kg, 25mg/kg, 50mg/kg) once daily for 13 consecutive days and a NSCLC mouse model (H3122 cells expressing the EML4−ALK fusion) for 19 consecutive days.; it is noticeable that it resulted in tumor regression with no signs of overt toxicity at a dose of 50mg/kg in Karpas-299 xenograft mouse model and tumor regressions at all doses tested (including the lowest 10 mg/kg dose) in a NSCLC mouse model^[8]. A retrospective multicentric study showed that Brigatinib exhibited clinical activity in ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. ^[9].
• 作用机制Brigatinib binds to and inhibits ALK kinase and ALK fusion proteins, which leads to the inhibition of ALK phosphorylation, thereby disrupting their signaling pathways and eventually inhibiting tumor cell growth in susceptible tumor cells^[10].

• 动物研究
  剂量	Mice: 10 mg/kg - 50 mg/kg[3] (p.o.), 75 mg/kg[4] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dose 4.5 mg/kg Administration p.o. V 2160.386 ± 802.252 L/kg T1/2 5.333 ± 1.647 h Tmax 6.333 ± 1.506 h CL 288.579 ± 94.167 L/h/kg Cmax 1.152 ± 0.258 μg/L AUC0→∞ 16.983 ± 5.365 μg/L*h AUC0→t 16.526 ± 5.355 μg/L*h

• 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
  NCT03087448	Non-small Cell Lung Cancer	Phase 1 Phase 2	Recruiting	March 2021	United States, California ... more >> UCSF Helen Diller Family Comprehensive Cancer Center Recruiting San Francisco, California, United States, 94115 Collapse <<
  NCT02784158	-	-	-	-	United States, California ... more >> UC San Diego Moores Cancer Center (Site 099) La Jolla, California, United States, 92093-0698 UCI Medical Center-Chao Family Comprehensive (Site 210) Orange, California, United States, 92868-3201 United States, Michigan Karmanos Cancer Institute (Site 070) Detroit, Michigan, United States, 48201 Collapse <<
  NCT03719898	Anaplastic Large Cell Lymphoma... more >>, ALK-Positive Collapse <<	Phase 2	Recruiting	December 2021	United States, Pennsylvania ... more >> Fox Chase Cancer Center Recruiting Philadelphia, Pennsylvania, United States, 19011 Contact: Carlyn Tan, MD    215-728-4300    carlynrose.tan@tuhs.temple.edu    Contact: Christiana Carns    215-214-6922    Christiana.Carns@tuhs.temple.edu Collapse <<

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• 参考文献

• [1] Zhang S, Anjum R, et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016 Nov 15;22(22):5527-5538.

  [2] Huang WS, Liu S, et al. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64.

  [3] Ali R, Arshad J, et al. Brigatinib for ALK-positive metastatic non-small-cell lung cancer: design, development and place in therapy. Drug Des Devel Ther. 2019 Feb 8;13:569-580.

  [4] Uchibori K, Inase N, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017 Mar 13;8:14768.

  [5] Wen J, Bao S, et al. A reliable and stable method for determination of brigatinib in rat plasma by UPLC-MS/MS: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Nov 15;1068-1069:84-89.

  [6] Katayama R. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.

  [7] Siaw JT. Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508.

  [8] Huang WS. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64. doi: 10.1021/acs.jmedchem.6b00306. Epub 2016 May 12.

  [9] Descourt R. Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study). Lung Cancer. 2019 Oct;136:109-114. doi: 10.1016/j.lungcan.2019.08.010. Epub 2019 Aug 14.

  [10] NCI Drug Dictionary

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