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

Acta Pharm Sin B. 2023 Dec;13(12):4748-4764. doi: 10.1016/j.apsb.2023.09.009.

Yingqiang Liu ¹, Zhengsheng Zhan ², Zhuang Kang ³, Mengyuan Li ¹, Yongcong Lv ², Shenglan Li ³, Linjiang Tong ¹, Fang Feng ¹, Yan Li ¹, Mengge Zhang ¹ ⁴, Yaping Xue ¹ ⁴ ⁵, Yi Chen ¹ ⁴, Tao Zhang ¹, Peiran Song ¹ ⁶, Yi Su ¹, Yanyan Shen ¹, Yiming Sun ¹, Xinying Yang ¹, Yi Chen ¹, Shanyan Yao ², Hanyu Yang ⁷, Caixia Wang ⁷, Meiyu Geng ¹ ⁴, Wenbin Li ³, Wenhu Duan ², Hua Xie ¹ ⁶ ⁴ ⁵, Jian Ding ¹ ⁴ ⁵

Affiliations

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 University of Chinese Academy of Sciences, Beijing 100049, China.
5 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
7 Shanghai Runshi Pharmaceutical Technology Co., Ltd., Shanghai 201218, China.

PMID: 38045044 DOI: 10.1016/j.apsb.2023.09.009

Abstract

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 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).

Keywords

Angiogenesis; CSF1R; Glioblastoma; Immune-checkpoint inhibitor; Macrophage; Small molecule inhibitor; Tumor microenvironment; VEGFR.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-161025

SYHA1813

99.46%, CSF1R Inhibitor

c-Fms; VEGFR

Cancer

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