title: A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models.
abstract: Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Ye_Xiang_S@lilly.com.
authors: Xiang S
authors: XS
authors: Ye
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Li
authors: L
authors: Fan
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Robert D
authors: RD
authors: Van Horn
authors: Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co. Ltd., Shizuoka, Japan.
authors: Ryuichiro
authors: R
authors: Nakai
authors: Medicinal Chemistry Research Laboratories, Kyowa Hakko Kirin Co. Ltd., Shizuoka, Japan.
authors: Yoshihisa
authors: Y
authors: Ohta
authors: Clinical Development Department 1, Development Division, Kyowa Hakko Kirin Co. Ltd., Shizuoka, Japan.
authors: Shiro
authors: S
authors: Akinaga
authors: Medicinal Chemistry Research Laboratories, Kyowa Hakko Kirin Co. Ltd., Shizuoka, Japan.
authors: Chikara
authors: C
authors: Murakata
authors: Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co. Ltd., Shizuoka, Japan.
authors: Yoshinori
authors: Y
authors: Yamashita
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Tinggui
authors: T
authors: Yin
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Kelly M
authors: KM
authors: Credille
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Gregory P
authors: GP
authors: Donoho
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Farhana F
authors: FF
authors: Merzoug
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Heng
authors: H
authors: Li
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Amit
authors: A
authors: Aggarwal
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Kerry
authors: K
authors: Blanchard
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Eric H
authors: EH
authors: Westin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C470243:KIF11 protein, human; D013449:Sulfonamides; D013830:Thiadiazoles; C000591843:litronesib; D016547:Kinesins