GRP94-selective therapeutics to treat cancer, glaucoma
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 (ACO1) can be used to develop an effective therapy for the treatment of metastatic cancer and/or primary open angle glaucoma.
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).