Quinazolin-2,4-dione-Based Hydroxamic Acids as Selective Histone Deacetylase‑6 Inhibitors for Treatment of Non-Small Cell Lung Cancer

We designed and synthesized quinazolin-2,4-dione-based
hydroxamic
acids to serve as selective competitive inhibitors of histone deacetylase-6
(HDAC6). The most potent and selective compound, 3d (IC50, 4 nM, HDAC6; IC50 > 10 μM, HDAC1),
substantially
increased acetylation of α-tubulin instead of histones in the
lung cancer cell line, LL2. Paclitaxel in combination with 3d had a synergistic anticancer effect on reduction of programmed death-ligand
1 expression in LL/2 cells. When given orally, 3d was
mainly found to locate in the liver and lungs, at a concentration
18- to 70-fold greater, respectively, than in plasma. As an orally
active HDAC6 inhibitor, 3d (20 mg/kg) potentiated paclitaxel
antitumor activity (percentage tumor growth inhibition, 67.5%) in
a xenograft syngeneic non-small cell lung cancer mouse model.