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

作　　者：Zongru Jiang Li Wang Xuesong Liu Cheng Chen Beilei Wang Wenliang Wang Chen Hu Kailin Yu Ziping Qi Qingwang Liu Aoli Wang Jing Liu Guangchen Hong Wenchao Wang Qingsong Liu 

机构地区：[1]High Magnetic Field Laboratory,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230031,China [2]University of Science and Technology of China,Hefei 230026,China [3]Precision Targeted Therapy Discovery Center,Institute of Technology Innovation,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230088,China [4]Precision Medicine Research Laboratory of Anhui Province,Hefei 230088,China [5]Qingdao Shinan District People's Hospital,Qingdao 266002,China [6]Institutes of Physical Science and Information Technology,Anhui University,Hefei 230601,China

出　　处：《Acta Pharmaceutica Sinica B》2020年第3期488-497,共10页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81773777,81673469,81603123,81803366);the China Postdoctoral Science Foundation(Grant Nos.2018T110634,2018M630720);the Anhui Province Postdoctoral Science Foundation(Grant No.2018B279);the CASHIPS Director’s Fund(Grant No.BJPY2019A03);the Key Program of 13th five-year plan,CASHIPS(Grant No.KP-2017-26).

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(CHMFLVEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L)and VEGFR2 autophosphorylation in cells(EC50s^100 nmol/L)as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=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 antiangiogenesis 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.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（CHMFLVEGFR2-002）,which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L) and VEGFR2 autophosphorylation in cells(EC50s～100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=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 antiangiogenesis 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.

关 键 词：Cancer VEGFR2 KINASE KINASE INHIBITOR ANGIOGENESIS INHIBITOR SELECTIVITY 

分 类 号：R96[医药卫生—药理学]