The Hsp90 heat shock protein is a 90 kDa molecular chaperone responsible for normal functions and pathogenic processes in cells. Its expression increases when the cell is exposed to stress conditions. It occurs in cells in four isoforms: in the cytoplasm as Hsp90α and Hsp90β, in the endoplasmic reticulum as Grp94, and in mitochondria as Trap1. Hsp90 represents an interesting target because of its important role in malignant cell transformation, development of neurogenerative diseases, viral and fungal infections.
Cancer is a complex family of diverse diseases associated with abnormal growth and cell division, leading to loss of control over growth, cell division, and death. Despite major advances in healthcare, cancer is still one of the leading causes of death in developed countries. Therefore, research into new anti-cancer drugs is of paramount importance to ensure successful treatment in the future. Hsp90 represents an interesting target for cancer therapy because it is ten times more abundant in cancer cells than in normal cells. Many Hsp90 inhibitors have been discovered in recent years, but none has yet come to market.
In this Master's thesis, we designed new selective Hsp90β inhibitors based on the known inhibitor IZS274 with the pyrrolamide scaffold, in which the carboxamide and piperidin-4-ol fragments were modified. We designed the analogs by first aligning all the crystal structures of the complexes between Hsp90 and the inhibitors and then, based on the overlap of the inhibitors with the binding conformation of IZS274 in the active site, replacing the carboxamide or piperidin-4-ol moiety with fragments from the crystal structures. By introducing new fragments, we aimed to investigate how the introduction of aromatic substituents, lipophilic substituents, and additional basic centers affects the affinity and selectivity of binding to Hsp90β. Molecular docking of the designed compounds in the binding site of Hsp90β was performed. Selected compounds with high value of scoring function were synthesized by researchers from the Faculty of Pharmacy. On the basis of the experimental Kd values, we found that compounds with aromatic substituents, despite the high assessment function, do not show affinity for Hsp90β, lipophilic substituents increased selectivity toward Hsp90β compared with Hsp90α, which are important findings for further design and development of selective Hsp90β inhibitors as potential anticancer agents.
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