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Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis.

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机构： [1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China [3]State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin, 300071, China [4]State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, 300071, China [5]Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

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关键词： CDK4 VEGFR2 Inhibitor Cancer

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Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study. Copyright © 2019 Elsevier Masson SAS. All rights reserved.

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出版当年[2019]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

第一作者：

第一作者机构： [1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China

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通讯作者：

通讯机构： [1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China [2]2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China [3]State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin, 300071, China [*1]Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China

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