Design, synthesis and biological evaluation of dual mTOR/HDAC6 inhibitors in MDA-MB-231 cells

The excessive activation of histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) signaling promotes tumor growth and progression. We proposed that dual targeting mTOR and HDAC inhibitors is a promising strategy for triple negative breast cancer (TNBC) treatment. In this study, a series of dual mTOR/ HDAC6 inhibitors were designed and synthesized by structure-based strategy. 10g was documented to be a potent dual mTOR/HDAC6 inhibitor with IC50 value of 133.7 nM against mTOR and 56 nM against HDAC6, presenting mediate antiproliferative activity in TNBC cells. Furthermore, we predicted the binding mode of 10g and mTOR/HDAC6 by molecule docking. In addition, 10g was documented to induce significant autophagy, apoptosis and suppress migration in MDA-MB-231 cells. Collectively, these findings revealed that 10g is a novel potent dual mTOR/HDAC6 inhibitor, which provides promising rationale for the combination of dual mTOR/ HDAC6 inhibitors for TNBC treatment.

Automated summary

The study suggests that dual targeting mTOR and HDAC inhibitors is a promising strategy for treating triple negative breast cancer. A potent dual mTOR/HDAC6 inhibitor 10g was designed and synthesized, showing antiproliferative activity in TNBC cells. Additionally, 10g was found to induce significant autophagy, apoptosis and suppress cell migration, providing a rationale for the use of dual mTOR/HDAC6 inhibitors for TNBC treatment.