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

Abstract

Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs. The diazepane aniline pyrimidine (4a) was identified as an initial hit (Aurora B IC₅₀ 6.9 µM). Molecular modeling guided SAR optimization lead to the identification of 8-fluorobenzodiazepine (6c) with single digit nM potency (Aurora B IC₅₀ 8 nM). In the antiproliferation assay 6c showed activity across the cell lines with IC₅₀ of 0.57, 0.42, and 0.69 µM for MCF-7, MDA-MB 231, and SkoV3 respectively. In the in vivo PK profile. 6c has shown higher bioavailability (73%) along with good exposure (AUC of 1360 ng.h/mL).

Keywords: Aurora kinase inhibitor; Oncology; Phenyldiazepine; Pyridodiazepine.