Start Date
2021
Description
Grp94 is one of four chaperones which belong to the Heat Shock Protein 90 (Hsp90) family. Hsp90 isoforms exist as homodimers and assist in the folding and maturation of over 400 client proteins. These proteins are highly sought-after therapeutic targets as they are known to chaperone misfolded proteins involved in various signaling pathways. During the protein folding cycle, ATP binds to the N-Terminal domain of Hsp90, which allows nascent polypeptides to undergo maturation. To prevent the folding and maturation of oncogenic proteins, researchers developed N-terminal inhibitors to prevent ATP binding. Unfortunately, these inhibitors (termed pan-inhibitors) were not isoform selective, which led to unwanted toxicities and side effects such as induction of Heat Shock Response (HSR) in clinical trials. To avoid these detriments, Grp94 selective inhibition was discovered as a desirable alternative for the inhibition of cancer metastasis.
Recommended Citation
Priebe, Zach; Pugh, Kyler; and Blagg, Brian S. J., "Synthesis and Biological Evaluation of Grp94 Selective Inhibitors" (2021). Summer Research. 53.
https://digitalcommons.calvin.edu/summer_research/2021/Posters/53
Included in
Synthesis and Biological Evaluation of Grp94 Selective Inhibitors
Grp94 is one of four chaperones which belong to the Heat Shock Protein 90 (Hsp90) family. Hsp90 isoforms exist as homodimers and assist in the folding and maturation of over 400 client proteins. These proteins are highly sought-after therapeutic targets as they are known to chaperone misfolded proteins involved in various signaling pathways. During the protein folding cycle, ATP binds to the N-Terminal domain of Hsp90, which allows nascent polypeptides to undergo maturation. To prevent the folding and maturation of oncogenic proteins, researchers developed N-terminal inhibitors to prevent ATP binding. Unfortunately, these inhibitors (termed pan-inhibitors) were not isoform selective, which led to unwanted toxicities and side effects such as induction of Heat Shock Response (HSR) in clinical trials. To avoid these detriments, Grp94 selective inhibition was discovered as a desirable alternative for the inhibition of cancer metastasis.