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

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

  • Mol Cancer Ther. 2019 Dec;18(12):2207-2219. doi: 10.1158/1535-7163.MCT-18-0529.
Jian Du 1 Lei Yan 2 Raquel Torres 3 Xueqian Gong 2 Huimin Bian 2 Carlos Marugán 3 Karsten Boehnke 3 Carmen Baquero 3 Yu-Hua Hui 2 Sonya C Chapman 4 Yanzhu Yang 2 Yi Zeng 2 Sarah M Bogner 2 Robert T Foreman 2 Andrew Capen 2 Gregory P Donoho 2 Robert D Van Horn 2 Darlene S Barnard 2 Jack A Dempsey 2 Richard P Beckmann 2 Mark S Marshall 5 Li-Chun Chio 2 Yuewei Qian 2 Yue W Webster 2 Amit Aggarwal 2 Shaoyou Chu 2 Shobha Bhattachar 2 Louis F Stancato 2 Michele S Dowless 2 Phillip W Iversen 2 Jason R Manro 2 Jennie L Walgren 2 Bartley W Halstead 2 Matthew Z Dieter 2 Ricardo Martinez 2 Shripad V Bhagwat 2 Emiko L Kreklau 2 Maria Jose Lallena 3 Xiang S Ye 2 Bharvin K R Patel 2 Christoph Reinhard 2 Gregory D Plowman 2 David A Barda 2 James R Henry 2 Sean G Buchanan 2 Robert M Campbell 2
Affiliations

Affiliations

  • 1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. du_jian@lilly.com.
  • 2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
  • 3 Eli Lilly and Company, Alcobendas (Madrid), Spain.
  • 4 Eli Lilly and Company, Windlesham, United Kingdom.
  • 5 Ped-Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract

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.

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