2. Academic Validation
  3. Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models

Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models

  • J Exp Clin Cancer Res. 2019 Aug 22;38(1):372. doi: 10.1186/s13046-019-1357-y.
Xia Peng 1 2,  Pengcong Hou 1 2,  Yi Chen 1 2,  Yang Dai 1 2,  Yinchun Ji 1 2,  Yanyan Shen 1 2,  Yi Su 1 2,  Bo Liu 1 2,  Yueliang Wang 1 2,  Deqiao Sun 1 2,  Yuchen Jiang 1 2,  Chuantao Zha 3,  Zuoquan Xie 1 2,  Jian Ding 1 2,  Meiyu Geng 4 5,  Jing Ai 6 7
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, No. 555 Zuchongzhi Road, Pudong New District, Shanghai, 201203, People's Republic of China.
  • 2 University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China.
  • 3 Shanghai HaiHe Pharmaceutical Co., Ltd, No. 421 Newton Road, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, 201203, People's Republic of China.
  • 4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, No. 555 Zuchongzhi Road, Pudong New District, Shanghai, 201203, People's Republic of China. mygeng@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China. mygeng@simm.ac.cn.
  • 6 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, No. 555 Zuchongzhi Road, Pudong New District, Shanghai, 201203, People's Republic of China. jai@simm.ac.cn.
  • 7 University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China. jai@simm.ac.cn.
PMID: 31438996 DOI: 10.1186/s13046-019-1357-y
Abstract

Background: The interaction between tumor cells and their immunosuppressive microenvironment promotes tumor progression and drug resistance. Thus, simultaneously targeting tumor cells and stromal cells is expected to have synergistic antitumor effects. Herein, we present for the first time a preclinical antitumor investigation of 3D185, a novel dual inhibitor targeting FGFRs, which are oncogenic drivers, and CSF-1R, which is the major survival factor for protumor macrophages.

Methods: The antitumor characteristics of 3D185 were assessed by a range of assays, including kinase profiling, cell viability, cell migration, immunoblotting, CD8+ T cell suppression, and in vivo antitumor efficacy, followed by flow cytometric and immunohistochemical analyses of tumor-infiltrating immune cells and endothelial cells in nude mice and immune-competent mice.

Results: 3D185 significantly inhibited the kinase activity of FGFR1/2/3 and CSF-1R, with equal potency and high selectivity over Other kinases. 3D185 suppressed FGFR signaling and tumor cell growth in FGFR-driven models both in vitro and in vivo. In addition, 3D185 could inhibit the survival and M2-like polarization of macrophages, reversing the immunosuppressive effect of macrophages on CD8+ T cells as well as CSF1-differentiated macrophage induced-FGFR3-aberrant Cancer cell migration. Furthermore, 3D185 inhibited tumor growth via remodeling the tumor microenvironment in TAM-dominated tumor models.

Conclusions: 3D185 is a promising antitumor candidate drug that simultaneously targets tumor cells and their immunosuppressive microenvironment and has therapeutic potential due to synergistic effects. Our study provides a solid foundation for the investigation of 3D185 in Cancer patients, particularly in patients with aberrant FGFR and abundant macrophages, who respond poorly to classic pan-FGFRi treatment.

Keywords

3D185; CSF-1R; FGFR; Kinase inhibitor; Tumor microenvironment.

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