Design, Synthesis and Evaluation of Non-Canonical Hsp90 Modulators

Abstract

Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90 C-terminus and induces degradation of Hsp90-dependent client proteins at ~700 &muM in breast cancer cells (SKBr3). Although many analogues of novobiocin have been synthesized in an attempt to improve upon this activity, it was only recently demonstrated that monomeric species can exhibit antiproliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated. Structure&ndashactivity relationships for novobiocin as an anti-cancer agent were elucidated through analogues that manifest low micromolar to nanomolar activity against several cancer cell lines. The compound that exhibited the best and most consistent activity has been further evaluated against a broader panel of cancers as well as taken into an in vivo model. Studies are ongoing to further refine the coumarin core, with the potential to replace it with a more suitable heterocyclic ring system. In addition to the coumarin portion, a noviose sugar and benzamide side chain are appended to the natural product. Because limited information exists regarding the role of the sugar appendage, a series of non-sugar derivatives was synthesized and evaluated to establish structure&ndashactivity relationships for the noviose region of novobiocin. These studies have produced simplified novobiocin analogues that manifest low micromolar activity against a panel of cancer cell lines. Likewise, studies have been executed to elucidate details concerning the benzamide side chain and its potential to make hydrophobic interactions with the binding pocket. The most promising compound from each of these series has demonstrated impressive activity against several cancer cell lines and have been evaluated in vivo. Efforts to understand the mechanism of action manifested by these diverse Hsp90 modulators are ongoing and have resulted in the existence of at least three distinct classes of Hsp90 C-terminal modulators. Moreover, collaborative studies with the NCI have revealed promising results with a compound that modulates Hsp90 through yet another disparate, but synergistic, mechanism. Through current studies, we hope to better solubilize the most potent compounds and advance novel Hsp90 modulators into clinical development.