2. Academic Validation
  3. Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer

  • J Med Chem. 2023 Jun 8;66(11):7421-7437. doi: 10.1021/acs.jmedchem.3c00090.
Jia He 1,  Luzhen Wang 2 3,  DaZhao Mi 1,  Tian Guan 1,  Wenjing Liu 4,  Peng He 1,  Haijun Gu 1,  Yuzhan Li 1,  Yangrui Peng 1,  Ai-Qun Jia 5,  Ceshi Chen 6 4 3,  Yihua Chen 1
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 School of Life Science, University of Science & Technology of China, Hefei 230027, Anhui, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.
  • 4 The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.
  • 5 Key Laboratory of Tropical Biological Resources of Ministry of Education, One Health Institute; School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 6 Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.
PMID: 37212861 DOI: 10.1021/acs.jmedchem.3c00090
Abstract

Triple-negative breast Cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of Cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149847
    Methuosis Inducer