Grp94-selective Therapeutics for the Treatment of Cancer or 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 can be used to develop an effective therapy for the treatment of metastatic cancer and/or primary open angle glaucoma (POAG).
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.
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).
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).
Drug development for the treatment of multiple diseases, including cancers, infections, neurodegenerative diseases, POAG, and diabetes.