ALK inhibitor 2 - CAS 761438-38-4
Catalog number: 761438-38-4
Category: Inhibitor
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ALK inhibitor 2 is a novel and selective inhibitor for the ALK kinase.
Benzenesulfonamide, 2-[[5-chloro-2-[[2-methoxy-4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]-N-methyl-
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1.Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).
Tu CH1,2, Lin WH1, Peng YH1, Hsu T1, Wu JS1, Chang CY1, Lu CT1, Lyu PC2, Shih C1, Jiaang WT1, Wu SY1. J Med Chem. 2016 Apr 28;59(8):3906-19. doi: 10.1021/acs.jmedchem.6b00106. Epub 2016 Apr 12.
Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.
2.Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial.
Kim DW1, Mehra R2, Tan DS3, Felip E4, Chow LQ5, Camidge DR6, Vansteenkiste J7, Sharma S8, De Pas T9, Riely GJ10, Solomon BJ11, Wolf J12, Thomas M13, Schuler M14, Liu G15, Santoro A16, Sutradhar S17, Li S17, Szczudlo T17, Yovine A18, Shaw AT19. Lancet Oncol. 2016 Mar 10. pii: S1470-2045(15)00614-2. doi: 10.1016/S1470-2045(15)00614-2. [Epub ahead of print]
BACKGROUND: ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.
3.Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
Inoue M1, Toki H2, Matsui J2, Togashi Y3, Dobashi A4, Fukumura R5, Gondo Y5, Minowa O2, Tanaka N6, Mori S6, Takeuchi K3, Noda T7. Carcinogenesis. 2016 Mar 10. pii: bgw028. [Epub ahead of print]
ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinctROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate thein vivooncogenic activities of one of the most frequently detected fusions,CD74-ROS1, as well as anotherSDC4-ROS1fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the twoROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2-4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden.
4.Metachronous primary uterine cancer surgically resected during Crizotinib treatment in a ALK-rearranged advanced lung adenocarcinoma.
Catino A1, Misino A1, Scattone A1, Caldarola L1, Petroni S1, Logroscino A1, Montagna ES1, Serio G1, Simone G1, Galetta D1. Transl Lung Cancer Res. 2016 Feb;5(1):145-9. doi: 10.3978/j.issn.2218-6751.2016.01.04.
Rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in 3% to 7% of non-small-cell lung cancers (NSCLCs). Patients harboring ALK rearrangements show very favourable outcomes if treated with targeted agents, among which crizotinib is the first and best studied. Crizotinib, an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases, is a very active and well tolerated drug. Nevertheless, the optimal therapy management with this new drug is still partially unknown, especially with regard to the safety of combined treatments. Recently, the integration of locoregional treatments has been proposed as a feasible multimodality strategy in selected patients with good clinical conditions and slow-growing or oligoprogressive disease. In this report, a case of advanced lung adenocarcinoma, progressed after first line chemotherapy and re-biopsied detecting ALK rearrangement, is described. During crizotinib treatment the primary lung tumor showed an excellent regression; meanwhile a major surgery for a metachronous uterine cancer was safely and successfully carried out.
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