Grp94-selective Inhibitors Manifest Broad Applications for the Inhibition of Metastatic Cancer
The technology presents a novel structural modification of an existing first generation Grp94 selective inhibitor to generate a second generation Grp94-specific scaffold which has greater affinity and selectivity compared to existing inhibitors and prevents unfavorable binding of other Hsp90 isoforms.
The endoplasmic reticulum Hsp90 paralog, Grp94 (glucose-regulated protein 94) is a master chaperone for multiple receptors including Toll-like receptors, Wnt coreceptors, and integrins. Despite its abundance and ubiquitous expression in most/all normal cells, unique expression patterns of Grp94 have been observed in multiple cancers. The discovery of more selective Grp94 inhibitors is highly desirable and is predicted to have implications in both drug development as well as the treatment of multiple disease states including cancer, inflammation, neurodegeneration and diabetes. KU researchers have developed unique Grp94-selective scaffold with improved affinity and selectivity. The lead compound showed potent antimigratory activity against multiple aggressive and metastatic cancers, consistent with Grp94’s role in the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins.
Preclinical studies demonstrate that Grp94 expression is closely linked to cancer growth and metastasis in melanoma, ovarian cancer, multiple myeloma, lung cancer, and inflammation-associated colon cancer.
How it works:
The design and development of the new scaffold was based on alteration of the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements.
Why it is better:
- Co-crystal structure available.
- The lead compound exhibits 540 nM affinity and 73-fold selectivity towards Grp94.
- The Grp94-selective inhibitor showed potent anti-migratory effect against multiple aggressive and metastatic cancers.
- The limited efficacy of Grp94 inhibition in non-aggressive cancers and the overexpression of Grp94 in aggressive cancers suggests that the efficacy of Grp94-selective inhibition correlates directly with the aggressiveness of a type of cancer.
- The scaffold that binds Grp94 in a conformation unfavorable for binding of other Hsp90 isoforms.
- Grp94 inhibition represents a non-toxic approach toward the treatment of some diseases (e.g. glaucoma).