Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma  

作　　者：Yingqiang Liu Zhengsheng Zhan Zhuang Kang Mengyuan Li Yongcong Lv Shenglan Li Linjiang Tong Fang Feng Yan Li Mengge Zhang Yaping Xue Yi Chen Tao Zhang Peiran Song Yi Su Yanyan Shen Yiming Sun Xinying Yang Yi Chen Shanyan Yao Hanyu Yang Caixia Wang Meiyu Geng Wenbin Li Wenhu Duan Hua Xie Jian Ding 

机构地区：[1]Division of Antitumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]Department of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Department of Neuro-oncology,Cancer Center,Beijing Tiantan Hospital,Capital Medical University,Beijing 100070,China [4]Shanghai Runshi Pharmaceutical Technology Co.,Ltd.,Shanghai 201218,China [5]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan 528400,China [6]University of Chinese Academy of Sciences,Beijing 100049,China [7]Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4748-4764,共17页药学学报（英文版）

基　　金：supported by grants from the Natural Science Foundation of China for Innovation Research Group(81821005);the National Natural Science Foundation of China(82273948 and 81573271);the"Personalized Medicines,Molecular Signaturebased Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020203 and XDA12020228,China);the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(2018ZX09711002-011-016);the Youth Innovation Promotion Association of CAS(2018324,China).

摘　　要：Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).

关 键 词：Small molecule inhibitor GLIOBLASTOMA VEGFR CSF1R Angiogenesis Macrophage Tumor microenvironment Immune-checkpoint inhibitor 

分 类 号：R73[医药卫生—肿瘤]