We have generated a series of drug-like compounds (the IHSF series) that potently disrupt proteostasis. Initially developed as effective inhibitors of heat shock factor 1 (HSF1) (1), the IHSF were found to cause hundreds of cellular proteins to unfold and aggregate at concentrations at which the compounds are cytotoxic (2). Among the denatured proteins are many components of the so-called proteostasis network, including HSF1, chaperones and co-chaperones, proteasome subunits and other components of the ubiquitin/proteasome system, translation initiation factors and proteins involved in autophagy. The compounds act as Michael acceptors reacting with nucleophilic groups on proteins (mainly thiols), thereby covalently modifying the proteins. Covalent modification of cellular proteins that leads to their unfolding also affects the proteins they interact with, resulting in the unfolding of the latter proteins as is evidenced by the observation that the majority of proteins that aggregate are not covalently modified. This effect magnifies the impact of the IHSF.
Cancer cells exhibit different sensitivities towards IHSF, presumably depending on the degree to which their proteostasis system is challenged by the aberrant expression of proteins. Particularly sensitive are multiple myeloma cells that synthesize excessive amounts of immunoglobulins, giving rise to increased production of unfolded proteins and defective ribosomal products. Certain triple-negative breast cancer cells are also highly sensitive to IHSF.
IHSF are therefore proposed as novel active agents for the therapy of multiple myeloma and certain other sensitive cancers. They may be employed to replace proteasome inhibitors in the large cohort of patients who developed resistance to these agents. Resistance to IHSF is expected to occur only rarely since these compounds act on the entire proteome and not on individual target proteins. IHSF may also be used in combination with proteasome inhibitors with which they synergize.
Our studies also revealed that certain natural products that are well-known in Asian medicine exhibit similar activities as IHSF. The advantages IHSF enjoy over these natural products are that they belong to a new class of drug-like molecules and that routes for their synthesis have been elaborated.
1. Vilaboa, N, Boré A, Martin-Saavedra F, Bayford M, Winfield N, Firth-Clark S, Kirton SB, Voellmy R (2017) Nucleic Acids Res. 45: 5797-817
2. Vilaboa N, Lopez J.A, de Mesa M, Eschudero-Duch C, Winfield N, Bayford M, Voellmy R. (2023) Pharmaceuticals. 16: 616