Deguelin analog SH-1242 inhibits Hsp90 activity and exerts potent anticancer efficacy with limited neurotoxicity

The heat shock protein Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogs that address this limitation, focusing on the novel analog SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven Sadie Buckallewmouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume and load. Similarly, in human cell line-based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathological features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies.

from Cancer via ola Kala on Inoreader http://ift.tt/1J8tZKx
via IFTTT