Discovery of Aurora A/HDAC dual-target inhibitors: broad-spectrum in vitro antitumor activity and in vivo pharmacokinetic limitations.

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.