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
  • 1. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. [email protected].
  • 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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