Design, Synthesis, and Biological Evaluation of Rapamycin Derivatives as the First Mammalian Target of Rapamycin and GLS1 Dual Inhibitors

The
mammalian target of rapamycin (mTOR) and glutaminase
1 (GLS1)
are key enzymes regulating metabolic reprogramming in breast cancer.
The first generation of mTOR and GLS1 dual inhibitors was designed
and synthesized on the basis of anticancer synergism. Compound 9d showed selective and potent antiproliferative activity
against all breast cancer cell lines and displayed potent inhibitory
activity against both mTOR (mTORC1 and mTORC2) and GLS1. Mechanism
studies revealed that 9d effectively modulated the level
of biomarkers and metabolites associated with mTOR and GLS1 inhibition
and triggered sustained and massive reactive oxygen species generation,
leading to cell death by autophagy, apoptosis, and ferroptosis. Moreover, 9d inhibited the metastasis, invasion, and angiogenesis of
breast cancer cells. In vivo experiments demonstrated that 9d significantly inhibited tumor growth and metastasis, without observable
toxicity. These findings proved mTOR/GLS1 dual inhibitors’
great therapeutic potential for breast cancer.