A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models

Ye Xiang S.; Fan Li; Van Horn Robert D.; Nakai Ryuichiro; Ohta Yoshihisa; Akinaga Shiro; Murakata Chikara; Yamashita Yoshinori; Yin Tinggui; Credille Kelly M.; Donoho Gregory P.; Merzoug Farhana F.; Li Heng; Aggarwal Amit; Blanchard Kerry; Westin Eric H.

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A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models

机译：一种新的EG5抑制剂（LY2523355）导致癌细胞中的有丝分裂和凋亡，并在异种移植肿瘤模型中显示出有效的抗肿瘤活性

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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. (C) 2015 AACR.

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来源
《Molecular cancer therapeutics》 |2015年第11期|共10页
作者
Ye Xiang S.; Fan Li; Van Horn Robert D.; Nakai Ryuichiro; Ohta Yoshihisa; Akinaga Shiro; Murakata Chikara; Yamashita Yoshinori; Yin Tinggui; Credille Kelly M.; Donoho Gregory P.; Merzoug Farhana F.; Li Heng; Aggarwal Amit; Blanchard Kerry; Westin Eric H.;
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作者单位

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Kyowa Hakko Kirin Co Ltd Drug Discovery Res Labs Shizuoka Japan;

Kyowa Hakko Kirin Co Ltd Med Chem Res Labs Shizuoka Japan;

Kyowa Hakko Kirin Co Ltd Dev Div Clin Dev Dept 1 Shizuoka Japan;

Kyowa Hakko Kirin Co Ltd Med Chem Res Labs Shizuoka Japan;

Kyowa Hakko Kirin Co Ltd Drug Discovery Res Labs Shizuoka Japan;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

Eli Lilly &

Co Lilly Res Labs Indianapolis IN 46285 USA;

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原文格式 PDF
正文语种 eng
中图分类肿瘤学;
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4. A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models [J] . Ye Xiang S., Fan Li, Van Horn Robert D., Molecular cancer therapeutics . 2015,第11期

机译：一种新的EG5抑制剂（LY2523355）导致癌细胞中的有丝分裂和凋亡，并在异种移植肿瘤模型中显示出有效的抗肿瘤活性
5. Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy [J] . Du Jian, Yan Lei, Torres Raquel, Molecular cancer therapeutics . 2019,第12期

机译：Aurora A选择抑制剂Ly3295668导致显性丝分裂骤停血，癌细胞的凋亡，并显示出有效的临床前抗肿瘤功效
6. Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor. [J] . Liu M, Yu H, Huo L, Biochemical Pharmacology . 2008,第2期

机译：使用特定的抑制剂验证有丝分裂驱动蛋白Eg5作为胰腺癌细胞和肿瘤异种移植物中的治疗靶标。
7. Induction of G2/M phase arrest and apoptosis by potent antitumor thirty-two-8-oxo-8H-acenaphtho1,2-bpyrrole-9-carbonitrile derivative in human cervix carcinoma cells [C] . rn, rn, rn Asian Pacific Confederation of Chemical Engineering congress . 2008

机译：强效抗肿瘤三十二-8-氧-8H-ac 1,2-b吡咯-9-腈衍生物在人宫颈癌细胞中诱导G2 / M期阻滞和凋亡
8. RS-41, A multi-targeted kinase inhibitor, induces cell cycle arrest and apoptosis in P53 mutant and wild type models of upper gastrointestinal cancers. [D] . Visal, Tanvi. 2017

机译：RS-41是一种多靶点激酶抑制剂，在上消化道癌的P53突变型和野生型模型中诱导细胞周期停滞和凋亡。
9. Plocabulin a novel tubulin inhibitor has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors [O] . Yannick Wang, Agnieszka Wozniak, Jasmien Wellens, 2020

机译：一种新型小管蛋白抑制剂具有胃肠道基质肿瘤的患者衍生的异种移植模型中具有有效的抗肿瘤活性
10. Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy [O] . Jian Du, Lei Yan, Raquel Torres, 2019

机译：Aurora选择性抑制剂Ly3295668导致癌细胞中的凋亡，癌细胞凋亡，并显示出有效的临床前抗肿瘤功效
11. B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models [R] . Gril, B., Palmieri, D., Qian, Y., 2011

机译：肿瘤细胞的B-Raf状态可能是pazopanib在异种移植肿瘤模型中抗肿瘤和抗血管生成作用的重要决定因素

A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models

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