PMID- 34139324
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20220104
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 47
DP  - 2021 Sep 1
TI  - Design, synthesis and biological evaluation of dual mTOR/HDAC6 inhibitors in 
      MDA-MB-231 cells.
PG  - 128204
LID - S0960-894X(21)00431-5 [pii]
LID - 10.1016/j.bmcl.2021.128204 [doi]
AB  - 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 IC(50) 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.
CI  - Copyright (c) 2021. Published by Elsevier Ltd.
FAU - Yao, Dahong
AU  - Yao D
AD  - 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.
FAU - Jiang, Jin
AU  - Jiang J
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, College of 
      Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 
      150081, PR China.
FAU - Zhang, Hualin
AU  - Zhang H
AD  - Department of Medicinal Chemistry and Natural Medicine Chemistry, College of 
      Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 
      150081, PR China.
FAU - Huang, Yelan
AU  - Huang Y
AD  - School of Pharmaceutical Sciences, Shenzhen University, Shenzhen 518118, PR 
      China.
FAU - Huang, Jian
AU  - Huang J
AD  - 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: huangjian@hrbmu.edu.cn.
FAU - Wang, Jinhui
AU  - Wang J
AD  - 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: wangjinhui@hrbmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210614
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.5.1.98 (HDAC6 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylase 6)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - *Drug Design
MH  - Drug Screening Assays, Antitumor
MH  - Histone Deacetylase 6/*antagonists & inhibitors/metabolism
MH  - Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - Protein Kinases/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - HDAC6
OT  - Migration
OT  - TNBC
OT  - mTOR
EDAT- 2021/06/18 06:00
MHDA- 2022/01/05 06:00
CRDT- 2021/06/17 20:13
PHST- 2021/02/19 00:00 [received]
PHST- 2021/05/27 00:00 [revised]
PHST- 2021/06/10 00:00 [accepted]
PHST- 2021/06/18 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2021/06/17 20:13 [entrez]
AID - S0960-894X(21)00431-5 [pii]
AID - 10.1016/j.bmcl.2021.128204 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2021 Sep 1;47:128204. doi: 10.1016/j.bmcl.2021.128204. Epub 
      2021 Jun 14.