2. Academic Validation
  3. Design, synthesis and biological evaluation of dual mTOR/HDAC6 inhibitors in MDA-MB-231 cells

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

  • Bioorg Med Chem Lett. 2021 Sep 1;47:128204. doi: 10.1016/j.bmcl.2021.128204.
Dahong Yao 1,  Jin Jiang 2,  Hualin Zhang 2,  Yelan Huang 3,  Jian Huang 4,  Jinhui Wang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, PR China.
  • 2 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China.
  • 3 School of Pharmaceutical Sciences, Shenzhen University, Shenzhen 518118, PR China.
  • 4 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China. Electronic address: [email protected].
PMID: 34139324 DOI: 10.1016/j.bmcl.2021.128204
Abstract

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.

Keywords

Apoptosis; Autophagy; HDAC6; Migration; TNBC; mTOR.

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