Discovery of a Novel Dual Histone Deacetylases (HDACs) and Mammalian Target of Rapamycin (mTOR) Target Inhibitor as a Promising Strategy for Cancer Therapy.

Discovery of a Novel Dual Histone Deacetylases (HDACs) and Mammalian Target of Rapamycin (mTOR) Target Inhibitor as a Promising Strategy for Cancer Therapy.

J Med Chem. 2019 Jan 10;:

Authors: Chen Y, Yuan X, Zhang W, Tang M, Zheng L, Wang F, Yan W, Yang S, Wei Y, He J, Chen L

Abstract
In the present study, a series of novel dual target HDAC and 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 IC50 of 1.2 nM and 0.19 nM. 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 anti-tumor activity with the combination medication in MM1S xenograft model with TGI of 72.5%, without causing significant loss of body weight and toxicity. All the results indicated that 12l could be a promising dual target inhibitor for treating hematologic malignancies.

PMID: 30629434 [PubMed - as supplied by publisher]

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