PMID- 34329994
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20220104
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 115
DP  - 2021 Oct
TI  - Alkaloid derivative ION-31a inhibits breast cancer metastasis and angiogenesis by 
      targeting HSP90alpha.
PG  - 105201
LID - S0045-2068(21)00578-2 [pii]
LID - 10.1016/j.bioorg.2021.105201 [doi]
AB  - Breast cancer has become the number one killer of women. In our previous study, 
      an active compound, ION-31a, with potential anti-metastasis activity against 
      breast cancer was identified through the synthesis of ionone alkaloid 
      derivatives. In the present study, we aimed to identify the therapeutic target of 
      ION-31a. We used a fluorescence tag labeled probe, molecular docking simulation, 
      and surface plasmon resonance (SPR) analysis to identify the target of ION-31a. 
      The main target of ION-31a was identified as heat shock protein 90 (HSP90). Thus, 
      ION-31a is a novel HSP90 inhibiter that could suppress the metastasis of breast 
      cancer and angiogenesis significantly in vitro and in vivo. ION-31a acts via 
      inhibiting the HSP90/hypoxia inducible factor 1 alpha (HIF-1alpha)/vascular 
      endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and 
      downregulating downstream signal pathways, including protein kinase B 
      (AKT)/mammalian target of rapamycin (mTOR), AKT2/protein kinase C epsilon (PKCzeta), 
      extracellular regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and 
      mitogen-activated protein kinase 14 (p38MAPK) pathways. ION-31a affects multiple 
      effectors implicated in tumor metastasis and has the potential to be developed as 
      an anti-metastatic agent to treat patients with breast cancer.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Ni, Tian-Wen
AU  - Ni TW
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
FAU - Duan, Xiao-Chuan
AU  - Duan XC
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China; Beijing 
      Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School 
      of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China; 
      Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking 
      University, Beijing 100191, PR China.
FAU - Wang, Meng
AU  - Wang M
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
FAU - Jia, Mei-Qi
AU  - Jia MQ
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
FAU - Chen, Ying
AU  - Chen Y
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
FAU - Yu, Yang
AU  - Yu Y
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
FAU - Qin, Nan
AU  - Qin N
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China. 
      Electronic address: qinnan@tmu.edu.cn.
FAU - Duan, Hong-Quan
AU  - Duan HQ
AD  - School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China; 
      Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 
      300070, PR China. Electronic address: duanhq@tmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210722
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Alkaloids)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Norisoprenoids)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Alkaloids/chemical synthesis/chemistry/*pharmacology
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Molecular Structure
MH  - Norisoprenoids/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Angiogenesis
OT  - HIF-1alpha/VEGF/VEGFR2 pathway
OT  - Heat shock protein 90alpha
OT  - ION-31a
OT  - Metastasis
OT  - Target identification
EDAT- 2021/07/31 06:00
MHDA- 2022/01/05 06:00
CRDT- 2021/07/30 20:24
PHST- 2021/04/13 00:00 [received]
PHST- 2021/07/18 00:00 [revised]
PHST- 2021/07/19 00:00 [accepted]
PHST- 2021/07/31 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2021/07/30 20:24 [entrez]
AID - S0045-2068(21)00578-2 [pii]
AID - 10.1016/j.bioorg.2021.105201 [doi]
PST - ppublish
SO  - Bioorg Chem. 2021 Oct;115:105201. doi: 10.1016/j.bioorg.2021.105201. Epub 2021 
      Jul 22.