PMID- 30629434
OWN - NLM
STAT- MEDLINE
DCOM- 20200303
LR  - 20211204
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 62
IP  - 3
DP  - 2019 Feb 14
TI  - Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin 
      Target Inhibitors as a Promising Strategy for Cancer Therapy.
PG  - 1577-1592
LID - 10.1021/acs.jmedchem.8b01825 [doi]
AB  - In the present study, a series of novel dual-target histone deacetylase (HDAC) 
      and mammalian target of rapamycin (mTOR) inhibitors were designed and synthesized 
      using pyrimidine-pyrazolyl pharmacophore to append HDAC recognition cap and 
      hydroxamic acid as a zinc-binding motif. Among them, 12l was the optimal lead 
      compound with potent inhibition activities against mTOR and HDAC1 with 
      half-maximal inhibitory concentration of 1.2 and 0.19 nM, respectively. Western 
      blot confirmed that 12l could upregulate acetylation of H3 and alpha-tubulin and 
      downregulate mTOR-related downstream mediators. 12l could also stimulate cell 
      cycle arrest in G(0)/G(1) phase and induce tumor cell apoptosis. 12l showed 
      comparable antitumor activity with the combination medication in MM1S xenograft 
      model with a tumor growth inhibitory rate of 72.5%, without causing significant 
      loss of body weight and toxicity. All of the results indicated that 12l could be 
      a promising dual target inhibitor for treating hematologic malignancies.
FAU - Chen, Yong
AU  - Chen Y
FAU - Yuan, Xue
AU  - Yuan X
FAU - Zhang, Wanhua
AU  - Zhang W
FAU - Tang, Minghai
AU  - Tang M
FAU - Zheng, Li
AU  - Zheng L
FAU - Wang, Fang
AU  - Wang F
FAU - Yan, Wei
AU  - Yan W
FAU - Yang, Shengyong
AU  - Yang S
AUID- ORCID: 0000-0001-5147-3746
FAU - Wei, Yuquan
AU  - Wei Y
FAU - He, Jun
AU  - He J
FAU - Chen, Lijuan
AU  - Chen L
AUID- ORCID: 0000-0002-8076-163X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190124
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.5.1.98 (HDAC1 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylase 1)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemical synthesis/metabolism/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Catalytic Domain
MH  - Cell Line, Tumor
MH  - Female
MH  - G1 Phase Cell Cycle Checkpoints/drug effects
MH  - Hematologic Neoplasms/drug therapy
MH  - Histone Deacetylase 1/chemistry/metabolism
MH  - Histone Deacetylase Inhibitors/chemical synthesis/metabolism/*therapeutic use
MH  - Humans
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Molecular Docking Simulation
MH  - Protein Binding
MH  - Protein Kinase Inhibitors/chemical synthesis/metabolism/*therapeutic use
MH  - Pyrazoles/chemical synthesis/metabolism/*therapeutic use
MH  - Pyrimidines/chemical synthesis/metabolism/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
EDAT- 2019/01/11 06:00
MHDA- 2020/03/04 06:00
CRDT- 2019/01/11 06:00
PHST- 2019/01/11 06:00 [pubmed]
PHST- 2020/03/04 06:00 [medline]
PHST- 2019/01/11 06:00 [entrez]
AID - 10.1021/acs.jmedchem.8b01825 [doi]
PST - ppublish
SO  - J Med Chem. 2019 Feb 14;62(3):1577-1592. doi: 10.1021/acs.jmedchem.8b01825. Epub 
      2019 Jan 24.