2. Academic Validation
  3. Discovery of potent ureido tetrahydrocarbazole derivatives for cancer treatments through targeting tumor-associated macrophages

Discovery of potent ureido tetrahydrocarbazole derivatives for cancer treatments through targeting tumor-associated macrophages

  • Eur J Med Chem. 2019 Dec 1;183:111741. doi: 10.1016/j.ejmech.2019.111741.
Haixiang Pei 1,  Juliang Qin 2,  Fengmian Wang 3,  Binghe Tan 1,  Zeda Zhao 1,  Yangrui Peng 1,  Fangfei Yu 1,  Ennian Li 4,  Mingyao Liu 1,  Rong Zhang 3,  Bo Liu 5,  Bing Du 6,  Yihua Chen 7
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China; Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600, Nanfeng Road, Fengxian District, Shanghai, 201499, China.
  • 3 Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600, Nanfeng Road, Fengxian District, Shanghai, 201499, China.
  • 4 The Second Clinical Medical College, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 5 The Second Clinical Medical College, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address: doctliu@263.net.
  • 6 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China; Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600, Nanfeng Road, Fengxian District, Shanghai, 201499, China. Electronic address: bdu@bio.ecnu.edu.cn.
  • 7 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China; Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600, Nanfeng Road, Fengxian District, Shanghai, 201499, China. Electronic address: yhchen@bio.ecnu.edu.cn.
PMID: 31605873 DOI: 10.1016/j.ejmech.2019.111741
Abstract

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for Cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.

Keywords

Cancer treatments; Repolarization; Tumor-associated macrophages; Ureido tetrahydrocarbazole.

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