Structural modification of a non-selective aminocyclohexanol-based heat shock protein 90 KDa (Hsp90) inhibitor led to a highly selective inhibitor of glucose regulated protein 94 kDa (Grp94). The new Grp94-selective inhibitor can be used to develop an effective therapy for the treatment of metastatic cancer and/or primary open angle glaucoma (POAG).
Hsp90 is a molecular chaperone crucial for the stability and function of many proteins essential for cell survival. Many Hsp90 client proteins, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are crucial to the pathogenesis of cancer, neurodegenerative diseases, and infection. Hsp90 inhibitors are currently being developed clinically as anti-cancer agents and have shown potential in molecularly deﬁned subgroups of solid tumors. However, these clinical Hsp90 inhibitors inhibit all four Hsp90 isoforms, which may limit their subsequent clinical translation. As a result, the development of isoform-selective Hsp90 inhibitors is being pursued to delineate the role of each Hsp90 isoform and to avoid the side effects associated with pan inhibition.
The endoplasmic reticulum-localized Hsp90 isoform, Grp94, is a master chaperone for multiple receptors, including toll-like receptors, Wnt co-receptors, and integrins. Despite its abundance and ubiquitous expression in most or all normal cells, Grp94 is closely linked to metastasis and poor survival, for which unique expression patterns of Grp94 have been observed in a variety of cancers. Moreover, Grp94 preserves mutant myocilin in cells, which results in degenerative eye disease POAG upon abnormal accumulation of the Grp94-dependent protein. Therefore, highly selective inhibitors of Grp94 are needed as therapeutics for the treatment of cancer and glaucoma without presenting the side effects that result from off-target inhibition of the other three Hsp90 isoforms.
Evaluation of the chaperone’s ATPase domain has revealed a conformational change that results in a hydrophobic cleft, which is structurally distinct from other Hsp90 isoforms that can be exploited to develop Grp94-selective therapeutics for the treatment of a variety of diseases. This invention describes a Grp94 hydrophobic cleft-selective binding agent as a potential therapeutic for cancer and/or glaucoma treatment.
Highly selective Grp94 inhibitors can be used to develop effective therapies to treat a variety of diseases, including cancer, degenerative diseases, and infections, characterized by increased Grp94 expression or aberrant expression of Grp94-dependent proteins without presenting the side effects that result from Hsp90 pan inhibition.
HOW IT WORKS:
The non-selective aminocyclohexanol-based Hsp90 inhibitor SNX-2112 was structurally modified to selectively occupy the Grp94 hydrophobic cleft, leading to the development of high-affinity, Grp94-selective inhibitor ACO1.
In vitro testing demonstrated that ACO1 binds selectively to the hydrophobic cleft of Grp94 with high affinity, leading to the inhibition of cancer cell migration and degradation of mutant myocilin. The invention, which represents a new, highly selective Grp94 inhibitor for the treatment of metastatic cancer and/or glaucoma, can potentially cause less toxicity and interference with Hsp90 function in normal cells, thus allowing for administration of higher drug doses in anticipation of greater anti-cancer activity with limited undesired outcomes. For example, the therapeutic benefits of ACO1 can be obtained without feedback upregulation of anti-apoptotic proteins (e.g., Akt) and resistance-mediating Hsp proteins (e.g., Hsp70).
WHY IT IS BETTER:
- Novel structural modification of an existing non-selective Hsp90 inhibitor (SNX-2112) generated a Grp94-selective scaffold (ACO1) that prevents unfavorable binding of other Hsp90 isoforms.
- Compared to known Grp94 inhibitors, ACO1 offers significantly greater selectivity (>200-fold) than, for example, purine-based ligands (100-fold selectivity).