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, 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.