Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy.

Autor:	Du J; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. du_jian@lilly.com., Yan L; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Torres R; Eli Lilly and Company, Alcobendas (Madrid), Spain., Gong X; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Bian H; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Marugán C; Eli Lilly and Company, Alcobendas (Madrid), Spain., Boehnke K; Eli Lilly and Company, Alcobendas (Madrid), Spain., Baquero C; Eli Lilly and Company, Alcobendas (Madrid), Spain., Hui YH; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Chapman SC; Eli Lilly and Company, Windlesham, United Kingdom., Yang Y; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Zeng Y; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Bogner SM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Foreman RT; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Capen A; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Donoho GP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Van Horn RD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Barnard DS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Dempsey JA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Beckmann RP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Marshall MS; Ped-Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana., Chio LC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Qian Y; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Webster YW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Aggarwal A; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Chu S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Bhattachar S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Stancato LF; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Dowless MS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Iversen PW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Manro JR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Walgren JL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Halstead BW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Dieter MZ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Martinez R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Bhagwat SV; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Kreklau EL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Lallena MJ; Eli Lilly and Company, Alcobendas (Madrid), Spain., Ye XS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Patel BKR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Reinhard C; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Plowman GD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Barda DA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Henry JR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Buchanan SG; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Campbell RM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2019 Dec; Vol. 18 (12), pp. 2207-2219. Date of Electronic Publication: 2019 Sep 17.
DOI:	10.1158/1535-7163.MCT-18-0529
Abstrakt:	Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo , persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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