Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent

doi:10.1016/j.apsb.2019.10.004

	Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent
	Jiang, Zongru 1,2; Wang, Li 1,2; Liu, Xuesong 1,2; Chen, Cheng 1,2; Wang, Beilei 1,2; Wang, Wenliang 1,2; Hu, Chen 1; Yu, Kailin 1; Qi, Ziping 1; Liu, Qingwang 3
刊名	ACTA PHARMACEUTICA SINICA B
	2020-03-01
卷号	10
关键词	Cancer VEGFR2 kinase Kinase inhibitor Angiogenesis Inhibitor selectivity
ISSN号	2211-3835
DOI	10.1016/j.apsb.2019.10.004
通讯作者	Hong, Guangchen(2297023869@qq.com) ; Wang, Wenchao(wwcbox@hmfl.ac.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要	Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC50 = 66 nmol/L) and VEGFR2 autophosphorylation in cells (EC(50)s similar to 100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI(50) = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
资助项目	National Natural Science Foundation of China[81773777] ; National Natural Science Foundation of China[81673469] ; National Natural Science Foundation of China[81603123] ; National Natural Science Foundation of China[81803366] ; China Postdoctoral Science Foundation[2018T110634] ; China Postdoctoral Science Foundation[2018M630720] ; Anhui Province Postdoctoral Science Foundation[2018B279] ; CASH-IPS Director's Fund[BJPY2019A03] ; Key Program of 13th five-year plan, CASHIPS[KP-2017-26]
WOS关键词	RENAL-CELL CARCINOMA ; SUNITINIB ; EFFICACY ; HYPOTHYROIDISM ; GROWTH ; SAFETY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000518042300008
资助机构	National Natural Science Foundation of China ; China Postdoctoral Science Foundation ; Anhui Province Postdoctoral Science Foundation ; CASH-IPS Director's Fund ; Key Program of 13th five-year plan, CASHIPS
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/103875]
专题	中国科学院合肥物质科学研究院
通讯作者	Hong, Guangchen; Wang, Wenchao; Liu, Qingsong
作者单位	1.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Peoples R China 3.Chinese Acad Sci, Precis Targeted Therapy Discovery Ctr, Inst Technol Innovat, Hefei Inst Phys Sci, Hefei 230088, Peoples R China 4.Precis Med Res Lab Anhui Prov, Hefei 230088, Peoples R China 5.Qingdao Shinan Dist Peoples Hosp, Qingdao 266002, Peoples R China 6.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Zongru,Wang, Li,Liu, Xuesong,et al. Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent[J]. ACTA PHARMACEUTICA SINICA B,2020,10.
APA	Jiang, Zongru.,Wang, Li.,Liu, Xuesong.,Chen, Cheng.,Wang, Beilei.,...&Liu, Qingsong.(2020).Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent.ACTA PHARMACEUTICA SINICA B,10.
MLA	Jiang, Zongru,et al."Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent".ACTA PHARMACEUTICA SINICA B 10(2020).