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

Wei Huang; Xihuan Sun; Yunzhan Li; Zhixiang He; Li Li; Zhou Deng; Xiaoxing Huang; Shang Han; Ting Zhang; Jiaji Zhong; Zheng Wang; Qingyan Xu; Jianming Zhang; Xianming Deng

doi:10.1021/acs.jmedchem.8b00753

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. Epub 2018 Jun 19.

Authors

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 Zhang⁴, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Cell Death / drug effects
Cell Line, Tumor
Drug Screening Assays, Antitumor / methods
Female
Half-Life
Humans
Mice, Inbred BALB C
Mice, Inbred ICR
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Vacuoles / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Small Molecule Libraries