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

Authors：He, Jia; Wang, Luzhen; Mi, DaZhao; Guan, Tian; Liu, Wenjing; He, Peng; Gu, Haijun; Li, Yuzhan; Peng, Yangrui; Jia, Ai-Qun; Chen, Ceshi^*; Chen, Yihua^*

Source：Journal of Medicinal Chemistry, 2023, 66(11): 7421-7437.

DOI：10.1021/acs.jmedchem.3c00090

• INDOLYL-PYRIDINYL-PROPENONES
• NONAPOPTOTIC-CELL-DEATH
• BIOLOGICAL EVALUATION
• HYPERSTIMULATION
• INHIBITORS

Triple-negativebreast cancer (TNBC) is a leading malignancyamongwomen that currently lack effective targeted therapeutic agents, andthe limitations of treatment have prompted the emergence of new strategies.Methuosis is a novel vacuole-presenting cell death modality that promotestumor cell death. Hence, a series of pyrimidinediamine derivativeswere designed and synthesized through evaluation of their abilitiesthat inhibit proliferation as well as induce methuosis against TNBCcells. Among them, JH530 showed excellent anti-proliferativeactivities and vacuolization capacity in TNBC. The mechanism researchindicated that JH530 caused cell death through inducingmethuosis of cancer cells. Furthermore, JH530 inhibitedtumor growth remarkably in the HCC1806 xenograft model without anapparent decrease in body weight. Overall, JH530 is amethuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides abasis for the future progress of more small molecules for TNBC treatment.

• Institution
  中国科学院; 海南大学