Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy

Yong Chen; Xue Yuan; Wanhua Zhang; Minghai Tang; Li Zheng; Fang Wang; Wei Yan; Shengyong Yang; Yuquan Wei; Jun He; Lijuan Chen

doi:10.1021/acs.jmedchem.8b01825

Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy

J Med Chem. 2019 Feb 14;62(3):1577-1592. doi: 10.1021/acs.jmedchem.8b01825. Epub 2019 Jan 24.

Authors

Yong Chen, Xue Yuan, Wanhua Zhang, Minghai Tang, Li Zheng, Fang Wang, Wei Yan, Shengyong Yang, Yuquan Wei, Jun He, Lijuan Chen

PMID: 30629434
DOI: 10.1021/acs.jmedchem.8b01825

Abstract

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 α-tubulin and downregulate mTOR-related downstream mediators. 12l could also stimulate cell cycle arrest in G₀/G₁ 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Catalytic Domain
Cell Line, Tumor
Female
G1 Phase Cell Cycle Checkpoints / drug effects
Hematologic Neoplasms / drug therapy
Histone Deacetylase 1 / chemistry
Histone Deacetylase 1 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylase Inhibitors / therapeutic use*
Humans
Mice, Inbred NOD
Mice, SCID
Molecular Docking Simulation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / chemical synthesis
Pyrazoles / metabolism
Pyrazoles / therapeutic use*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / therapeutic use*
TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
TOR Serine-Threonine Kinases
HDAC1 protein, human
Histone Deacetylase 1