2. Academic Validation
  3. Discovery and Identification of Small Molecules as Methuosis Inducers with in Vivo Antitumor Activities

Discovery and Identification of Small Molecules as Methuosis Inducers with in Vivo Antitumor Activities

  • J Med Chem. 2018 Jun 28;61(12):5424-5434. doi: 10.1021/acs.jmedchem.8b00753.
Wei Huang 1 2,  Xihuan Sun 1 2,  Yunzhan Li 1 2,  Zhixiang He 1 2,  Li Li 1 2,  Zhou Deng 1 2,  Xiaoxing Huang 1 2,  Shang Han 1 2,  Ting Zhang 1 2,  Jiaji Zhong 1 2 3,  Zheng Wang 1 2,  Qingyan Xu 1 2,  Jianming Zhang 4,  Xianming Deng 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences , Xiamen University , Xiamen , Fujian 361102 , China.
  • 2 State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products , Xiamen University , Xiamen , Fujian 361102 , China.
  • 3 Medical College of Xiamen University , Xiamen , Fujian 361102 , China.
  • 4 Cutaneous Biology Research Center, Massachusetts General Hospital , Harvard Medical School , Boston , Massachusetts 02129 , United States.
PMID: 29878764 DOI: 10.1021/acs.jmedchem.8b00753
Abstract

Methuosis is a novel nonapoptotic mode of cell death characterized by vacuole accumulation in the cytoplasm. In this article, we describe a series of azaindole-based compounds that cause vacuolization in MDA-MB-231 cells. The most potent vacuole inducer, compound 13 (compound 13), displayed differential cytotoxicities against a broad panel of Cancer cell lines, such as MDA-MB-231, A375, HCT116, and MCF-7, but it did not inhibit the growth of the nontumorigenic epithelial cell line MCF-10A. A mechanism study confirmed that the cell death was caused by inducing methuosis. Furthermore, compound 13 exhibited substantial pharmacological efficacy in the suppression of tumor growth in a xenograft mouse model of MDA-MB-231 cells without apparent side effects, which makes this compound the first example of a methuosis inducer with potent in vivo efficacy. These results demonstrate that methuosis inducers might serve as novel therapeutics for the treatment of Cancer.

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