Heteroarene-fused anthraquinone derivatives as potential modulators for human aurora kinase B

The quest for effective anticancer therapeutics continues to be extensively pursued. Over the past century, several drugs have been developed, however, a majority of these drugs have a poor therapeutic index and increased toxicity profile. Hence, there still exists ample opportunity to discover safe and effective anticancer drugs. Aurora Kinase B (AurB), a member of the Aurora kinase family and a key regulator of mitotic cell division, is found to be frequently overexpressed in a variety of human cancers and has thus emerged as an attractive target for the design of anticancer therapeutics. In the present study, a structure-based scaffold hopping approach was utilized to modify the heterocyclic moiety of (S)-3-(3-aminopyrrolidine-1-carbonyl)-4,11-dihydroxy-2-methylanthra [2,3-b]furan-5,10-dione (anthrafuran 1) to generate a series of heteroarene-fused anthraquinone derivatives, which were then subjected to virtual screening for the identification of potential AurB inhibitors. The obtained hits were subsequently synthesized and evaluated by using a combination of in silico and biophysical techniques for elucidating their in vitro binding and inhibition activity with recombinantly expressed AurB. Four identified hits presented an improved binding profile as compared to their parent analog anthrafuran 1. One derivative, anthrathiophene 2 demonstrated excellent in vitro inhibition of AurB (7.3 mu M). (C) 2020 Published by Elsevier B.V.

Automated summary

This study utilized a structure-based scaffold hopping approach to design a series of heteroarene-fused anthraquinone derivatives, which were then subjected to virtual screening and experimental evaluation to identify a compound that showed excellent in vitro inhibition of AurB.