The 90 kDa heat shock proteins (Hsp90) are responsible for the maturation of approximately 200 client protein substrates, most of which are associated with signaling cascades that regulate cellular growth and proliferation. Therefore, Hsp90 inhibition provides a novel approach toward the treatment of cancer as numerous signaling cascades can be derailed through inhibition of the Hsp90-dependent protein folding process. In this application, we propose to develop selective inhibitors of the Hsp90 Isoforms, Grp94, Hsp90?, and Hsp90?, using a structure-guided approach. In addition, we will perform side by side evaluation of these compounds against pan-inhibitors both in vitro and in vivo to validate our approach. Together, these methods will provide a new approach for selective inhibition of Hsp90 and will provide a new paradigm for anti-cancer drug development.
The development of cancer chemotherapeutics that exhibit minimal toxicity represents an emerging paradigm in medicinal chemistry/drug design. To diminish the detrimental properties associated with panHsp90 Inhibition, we will develop isoform-selective inhibitors of Hsp90 based on a rational drug design approach.
| Sanchez, Jaquelyn N; Wang, Ton; Cohen, Mark S (2018) BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. Drugs 78:549-566 |
| Subramanian, C; Kovatch, K J; Sim, M W et al. (2017) Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells. Neoplasia 19:1003-1011 |
| Khandelwal, Anuj; Crowley, Vincent M; Blagg, Brian S J (2017) Resorcinol-Based Grp94-Selective Inhibitors. ACS Med Chem Lett 8:1013-1018 |
| Crowley, Vincent M; Huard, Dustin J E; Lieberman, Raquel L et al. (2017) Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. Chemistry 23:15775-15782 |
