Discovery of Aurora A/HDAC dual-target inhibitors: broad-spectrum in vitro antitumor activity and in vivo pharmacokinetic limitations.
TL;DR
Z20 is a potent Aurora A/HDAC dual-target inhibitor in vitro, while its pharmacokinetic defects limit clinical potential, which highlights the necessity of optimizing pharmacokinetic profiles for translating in vitro potency to in vivo efficacy.
Abstract
This study aimed to develop dual-target inhibitors against Aurora A and HDACs, and identified Z20 as the optimal candidate via in vitro screening. Z20 showed non-selective HDAC inhibitory activity and potent anti-tumor effects, significantly inhibiting the growth of 5 tumor cell lines (including Jurkat, HCT116) with efficacy superior to positive control CAM2602. It dose-dependently induced apoptosis and G2/M phase arrest in Jurkat and HCT116 cells, and specifically regulated the Aurora A/HDAC pathway by downregulating p-Aurora A and upregulating HDAC substrates Ac-H3/Ac-α-tubulin. However, Z20 exhibited poor in vivo efficacy (TGI: 47.2% vs. 62.7% for CAM2602) in NOG mice bearing Jurkat xenografts. Metabolic and pharmacokinetic evaluations revealed that Z20 had unfavorable properties: extremely short half-life (17.6 min), high intrinsic clearance (0.08 mL min-1 mg-1), and low oral bioavailability (0.3%), which accounted for its suboptimal in vivo performance. In conclusion, Z20 is a potent Aurora A/HDAC dual-target inhibitor in vitro, while its pharmacokinetic defects limit clinical potential. This study highlights the necessity of optimizing pharmacokinetic profiles for translating in vitro potency to in vivo efficacy.