Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Aurora B kinase is crucial for mitosis and frequently overexpressed in various cancers.
• Targeting Aurora B is a promising strategy for developing novel anti-cancer therapeutics.

Purpose of the Study:

• To design, synthesize, and evaluate novel phenyl/pyridine diazepine analogs as Aurora B inhibitors.
• To identify potent and selective inhibitors with potential anti-cancer activity.

Main Methods:

• Structure-based drug design and medicinal chemistry approaches were employed.
• In vitro kinase inhibition assays (IC50 determination) were performed for Aurora B.
• Antiproliferation assays were conducted across multiple cancer cell lines (MCF-7, MDA-MB 231, SkoV3).
• In vivo pharmacokinetic (PK) profiling was assessed.

Main Results:

• An initial hit, diazepane aniline pyrimidine (4a), showed moderate Aurora B inhibition (IC50 = 6.9 µM).
• Structure-activity relationship (SAR) optimization led to the identification of 8-fluorobenzodiazepine (6c) with potent Aurora B inhibition (IC50 = 8 nM).
• Compound 6c exhibited significant antiproliferative activity (IC50 = 0.42–0.69 µM) across tested cancer cell lines.
• Compound 6c demonstrated favorable in vivo PK properties, including 73% bioavailability and good exposure (AUC = 1360 ng·h/mL).

Conclusions:

• 8-Fluorobenzodiazepine (6c) is a potent Aurora B inhibitor with significant anti-cancer potential.
• The developed compounds represent promising leads for further investigation as anti-cancer agents targeting Aurora B.