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

文献类型：期刊论文

作者Liu, Yingqiang7; Zhan, Zhengsheng6; Kang, Zhuang5; Li, Mengyuan7; Lv, Yongcong6; Li, Shenglan5; Tong, Linjiang7; Feng, Fang7; Li, Yan7; Zhang, Mengge2,7
刊名ACTA PHARMACEUTICA SINICA B
出版日期2023-12-01
卷号13期号:12页码:4748-4764
关键词Small molecule inhibitor Tumor microenvironment Immune-checkpoint immune-deficient mouse models including temozolomide (TMZ) insensitive tumors. Notably
ISSN号2211-3835
DOI10.1016/j.apsb.2023.09.009
通讯作者Li, Wenbin(liwenbin@ccmu.edu.cn) ; Duan, Wenhu(whduan@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn)
英文摘要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 CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R 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 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).
WOS关键词MACROPHAGE POLARIZATION ; KINASE INHIBITOR ; MYELOID CELLS ; TUMOR ; ANGIOGENESIS ; REVEALS
资助项目Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[82273948] ; National Natural Science Foundation of China[81573271] ; Chinese Academy of Sciences (China)[XDA12020203] ; Chinese Academy of Sciences (China)[XDA12020228] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-011-016] ; Youth Innovation Promotion Association of CAS (China)[2018324]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001125824200001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/308284]  
专题新药研究国家重点实验室
通讯作者Li, Wenbin; Duan, Wenhu; Xie, Hua; Ding, Jian
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Shanghai Runshi Pharmaceut Technol Co Ltd, Shanghai 201218, Peoples R China
5.Capital Med Univ, Beijing Tiantan Hosp, Canc Ctr, Dept Neurooncol, Beijing 100070, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Yingqiang,Zhan, Zhengsheng,Kang, Zhuang,et al. Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma[J]. ACTA PHARMACEUTICA SINICA B,2023,13(12):4748-4764.
APA Liu, Yingqiang.,Zhan, Zhengsheng.,Kang, Zhuang.,Li, Mengyuan.,Lv, Yongcong.,...&Ding, Jian.(2023).Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma.ACTA PHARMACEUTICA SINICA B,13(12),4748-4764.
MLA Liu, Yingqiang,et al."Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma".ACTA PHARMACEUTICA SINICA B 13.12(2023):4748-4764.

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来源：上海药物研究所

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