Design, Synthesis and Biological Evaluation of Ring-constrained and Biphenyl Derivatives as Hsp90 C-terminal Inhibitors

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a pivotal role in protein homeostasis in responses to cellular stress. Hsp90 regulates the conformational maturation, activation, and integrity of a wide array of client proteins, including oncogenic proteins (Her2, Raf1, Akt, CDK4 etc.) associated with all six hallmarks of cancer. Consequently, Hsp90 inhibition offers a unique opportunity for the simultaneous degradation of multiple anti-cancer targets and hence, for the development of cancer chemotherapeutics. Hsp90 exists as a homodimer with each monomer consisting of a druggable domain; the N-terminal domain, the middle domain, and the C-terminus. The majority of research has focused on development of Hsp90 N-terminal inhibitors. In fact, all Hsp90 inhibitors in clinical trials belong to this class. One of the major drawbacks associated with N-terminal inhibitors is the concomitant induction of the pro-survival response, which results in an upregulation of Hsp's and affects the dosing schedule. As a result, alternative strategies are sought for the development of future Hsp90 inhibitors. Over the last decade, Hsp90 C-terminal inhibitors have emerged an attractive alternative for Hsp90 modulation. These inhibitors exhibit similar inhibitory activity to N-terminal inhibitors, but do not induce the pro-survival response and could potentially circumvent the clinical limitations imposed on N-terminal Inhibitors. Presented herein are the design, synthesis and biological evaluation of ring-constrained novobiocin analogues that provide new insights into the Hsp90 C-terminal binding pocket and SAR's that can be used for future analog development. In addition, identification of a novel class of Hsp90 inhibitors is discussed. These new agents provide a platform upon which future Hsp90 inhibitors can be built upon