Identifying Small Molecules To Probe the Role of Heat Shock Factor 1 in Cancer
The heat shock response (HSR) is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding environment through the induction of heat shock proteins (HSP) such as HSP70 and HSP90, but as more recent work has shown to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this ancient response is regulated primarily more ..
The heat shock response (HSR) is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding environment through the induction of heat shock proteins (HSP) such as HSP70 and HSP90, but as more recent work has shown to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this ancient response is regulated primarily by Heat Shock Factor 1 (HSF-1), a transcription factor whose mode of action has been conserved in broad outline across all eukaryotes. Acting at a global systems level, HSF-1 function permits cells to survive the drastic imbalances in signaling and profound alterations in DNA, protein and energy metabolism that occur during malignant transformation. Knockdown of HSF-1 expression using genetic techniques is well tolerated in normal cells and even in whole animals but, malignant cells display a profound dependence on this "non-oncogene." The regulation of HSF-1 function is complex and involves a cascade of multiple post-translational modifications that may provide biologically interesting and therapeutically tractable targets for specific inhibition of HSF-1 function. We propose to identify specific inhibitors of HSF-1 activation to further probe its role in cancer biology.
None of the currently available inhibitors of HSF-1 activation has been shown to act upon HSF1 directly and all of these compounds
demonstrate prominent non-HSF1 dependent effects unique to their particular modes of action. Hence, the limited specificity, poorly defined mechanisms of action and possible effects as general transcription and translation inhibitors rather than as specific HSF-1 inhibitors highlight the unmet need for the identification of more specific inhibitors of HSF-1. Therefore, this project seeks to identify specific inhibitors of HSF1 using an optimized high throughput cell-based reporter gene assay. Then to evaluate the potency, specificity and mode of action of compounds using secondary and counter-screening assays in order to guide the selection of screen hits for analog synthesis and support their optimization into useful chemical biological probes.
a. IC50 < 10uM
b. Specific inhibitor of HSF-1, not a general transcription or translation inhibitor. We would like to see 10-fold or greater specific inhibition over general transcription inhibition or translation.
c. Non-luciferase quenching.
d. Minimal cytotoxicity to non-transformed cells at 5-fold the concentration determined to inhibit HSF1 activation by 50% (IC50)
e. Inhibition of cancer cell growth/survival with 10-fold greater potency than the growth/survival of non-cancer cells
f. Inhibition of oncogene-mediated foci formation
Keywords: HSF-1, Heat Shock Response, Cancer
Primary Collaborators : Luke Whitesell, Whitehead Inst., firstname.lastname@example.org, 617-452-3542, Cambridge, MA,