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

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.