proteotoxic

The published study examined the ability of the Company's prototype Curaxin (CBLC102, or quinacrine) to inhibit heat shock response, a major adaptive pro-survival pathway that rescues cells from stressful conditions involving accumulation of misfolded proteins (known as proteotoxic stress).

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However, these screens often result in the identification of compounds that promote HSF1 activation through the proteotoxic accumulation of unfolded proteins or through the inhibition of Hsp90, a central chaperone involved in cell growth, signaling, and proliferation

PLoS Biology: New Articles Daniel W. Neef et al. 2010

In response to proteotoxic stress or pharmacological inhibitors of Hsp90, this complex dissociates, resulting in the multimerization of HSF1

PLoS Biology: New Articles Daniel W. Neef et al. 2010

These observations provide additional evidence that HSF1A activates HSF1 in a manner that is mechanistically distinct from a proteotoxic stress.

PLoS Biology: New Articles Daniel W. Neef et al. 2010

As such, previous screens for small molecule activators of HSF1 in mammalian cells have identified molecules that elevate protein chaperone expression through the imposition of proteotoxic stress conditions, such as direct protein thiol oxidation

PLoS Biology: New Articles Daniel W. Neef et al. 2010

Because most metazoan chaperones stabilize, but do not disaggregate misfolded proteins, these results are consistent with the oligomeric precursors of amyloid fibrils being toxic to neurons, rather than the aggregates themselves In eukaryotic cells, multiple genes encoding protein chaperones are coordinately transcriptionally activated in response to proteotoxic conditions, such as acute increases in temperature, by the heat shock transcription factor 1 (HSF1) protein and cis-acting promoter sequences called heat shock elements (HSEs) [18] -.

PLoS Biology: New Articles Daniel W. Neef et al. 2010

Human HSF1 is not activated in yeast by proteotoxic agents.

PLoS Biology: New Articles Daniel W. Neef et al. 2010

This screen, insensitive to established proteotoxic agents and Hsp90 inhibitors, identifies novel small molecules that activate HSF1 in the amelioration of neurodegenerative phenotypes in metazoan models of polyQ-based disease.

PLoS Biology: New Articles Daniel W. Neef et al. 2010

Although the precise mechanism by which HSF1A activates human HSF1 is not yet understood, several observations suggest that HSF1A does not activate HSF1 through the inhibition of Hsp90 activity nor through the imposition of a proteotoxic stress.

PLoS Biology: New Articles Daniel W. Neef et al. 2010

Neuronal tissues are exquisitely sensitive to defective protein folding, and the accumulation of misfolded proteins is proteotoxic due to dominant effects of insolubility, inappropriate intermolecular interactions, and long half-lives.

PLoS Biology: New Articles Daniel W. Neef et al. 2010