FH-2001 is a novel FGFR/VEGFR dual inhibitor with immune-modulating activity.

IF 2.2 4区 医学 Q3 ONCOLOGY
Anti-Cancer Drugs Pub Date : 2025-10-01 Epub Date: 2025-06-24 DOI:10.1097/CAD.0000000000001743
Aiguo Liu, Longfei Huang, Xin Gao, Lei Liu, Xiang Li, Xiaohong Yu, Chunyan Zhao
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引用次数: 0

Abstract

Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed and approved for use in solid cancers; however, there is still a high unmet medical need for new agents that have a more powerful antitumor activity and a broader antitumor spectrum. Here, we report the discovery of FH-2001, a novel and potent FGFR/VEGFR dual inhibitor, with additional activity of modulating programmed cell death ligand 1 (PD-L1) gene expression. In biochemical assays, FH-2001 showed potent inhibition of FGFR1, 2, 3, and 4, with half-maximal inhibitory concentration (IC 50 ) of 0.2, 0.2, 0.4, and 2.0 nM, respectively, and VEGFR1, 2, and 3, with IC 50 values of 2.0, 0.3, and 0.5 nM, respectively. FH-2001 significantly suppressed the cell growth of FGFR- or VEGFR-driven cancer cell lines. In representative cell line- and patient-derived tumor xenografts with aberrant FGFR or VEGFR signaling, FH-2001 substantially inhibited tumor growth. Furthermore, FH-2001 demonstrated marked antitumor activities when treated alone or combined with PD-L1 or PD-1 antibody in syngeneic mouse models. Flow cytometric analysis revealed that FH-2001 alone or in combination with anti-PD-L1 increased T and natural killer cells and decreased myeloid cells in the tumor microenvironment. Mechanistically, FH-2001 treatment dramatically reduced c-Myc and PD-L1 mRNA and protein levels in a dose-dependent manner in vitro . Taken together, FH-2001 is a promising dual-target inhibitor of FGFR and VEGFR and also modulates cancer immunity, while its robust antitumor activity positions it as a potentially class-leading anticancer agent.

FH-2001是一种具有免疫调节活性的新型FGFR/VEGFR双抑制剂。
多种癌症是由异常成纤维细胞生长因子受体(FGFR)信号和血管内皮生长因子受体(VEGFR)相关的血管生成驱动的。一些靶向FGFR和VEGFR的治疗药物已被开发并批准用于实体癌症;然而,对于具有更强的抗肿瘤活性和更广泛的抗肿瘤谱的新药物,仍有很高的未满足的医学需求。在这里,我们报告了FH-2001的发现,FH-2001是一种新型的有效的FGFR/VEGFR双重抑制剂,具有调节程序性细胞死亡配体1 (PD-L1)基因表达的额外活性。在生化试验中,FH-2001显示出对FGFR1、2、3和4的有效抑制,其半数最大抑制浓度(IC50)分别为0.2、0.2、0.4和2.0 nM,对VEGFR1、2和3的IC50分别为2.0、0.3和0.5 nM。FH-2001显著抑制FGFR-或vegfr驱动的癌细胞系的细胞生长。在具有代表性的具有异常FGFR或VEGFR信号的细胞系和患者来源的肿瘤异种移植物中,FH-2001显著抑制肿瘤生长。此外,在同基因小鼠模型中,FH-2001在单独或与PD-L1或PD-1抗体联合治疗时显示出显著的抗肿瘤活性。流式细胞术分析显示,FH-2001单独或与抗pd - l1联合使用可增加肿瘤微环境中的T细胞和自然杀伤细胞,减少骨髓细胞。机制上,FH-2001治疗显著降低体外c-Myc和PD-L1 mRNA和蛋白水平,呈剂量依赖性。综上所述,FH-2001是一种很有前景的FGFR和VEGFR双靶点抑制剂,也可以调节癌症免疫,同时其强大的抗肿瘤活性使其成为一种潜在的领先抗癌药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Anti-Cancer Drugs
Anti-Cancer Drugs 医学-药学
CiteScore
3.80
自引率
0.00%
发文量
244
审稿时长
3 months
期刊介绍: Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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