Supplementary Tables from Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy
posted on 2023-04-03, 15:28authored byJian Du, Lei Yan, Raquel Torres, Xueqian Gong, Huimin Bian, Carlos Marugán, Karsten Boehnke, Carmen Baquero, Yu-Hua Hui, Sonya C. Chapman, Yanzhu Yang, Yi Zeng, Sarah M. Bogner, Robert T. Foreman, Andrew Capen, Gregory P. Donoho, Robert D. Van Horn, Darlene S. Barnard, Jack A. Dempsey, Richard P. Beckmann, Mark S. Marshall, Li-Chun Chio, Yuewei Qian, Yue W. Webster, Amit Aggarwal, Shaoyou Chu, Shobha Bhattachar, Louis F. Stancato, Michele S. Dowless, Phillip W. Iversen, Jason R. Manro, Jennie L. Walgren, Bartley W. Halstead, Matthew Z. Dieter, Ricardo Martinez, Shripad V. Bhagwat, Emiko L. Kreklau, Maria Jose Lallena, Xiang S. Ye, Bharvin K.R. Patel, Christoph Reinhard, Gregory D. Plowman, David A. Barda, James R. Henry, Sean G. Buchanan, Robert M. Campbell
Supplementary Tables
Funding
Eli Lilly & Company
History
ARTICLE 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.