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
  • 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.