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

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, showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that caused cell death through inducing methuosis of cancer cells. Furthermore, inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, is a methuosis inducer that displayed remarkable suppression of TNBC growth and , which provides a basis for the future progress of more small molecules for TNBC treatment.