3D-QSAR-Assisted Design, Synthesis, and Evaluation of Novobiocin Analogues

Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure activity relationships. On the basis of the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure activity (3D QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced antiproliferative activity at midnanomolar concentrations, which results through Hsp90 inhibition.