Second Generation Grp94‐Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. Issue 62 (27th September 2017)

• Record Type: Journal Article
• Authors: Crowley, Vincent M.; Huard, Dustin J. E.; Lieberman, Raquel L.; Blagg, Brian S. J.
• Is Part Of: Chemistry. Volume 23:Issue 62(2017)
• Page Start: 15775
• Page End: 15782
• Publication Date: 2017-09-27
• Subjects: cancer -- Grp94 -- proteins -- medicinal chemistry -- metastatic; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201703398
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis ‐amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis ‐amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure–activity relationship studies led to the discovery of compound30, which exhibits 540 nm affinity and 73‐fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94‐selective inhibitor30 was shown to exhibit potent anti‐migratory effects against multiple aggressive and metastatic cancers. Abstract : Stop right there ! Modifications to the cis ‐amide bioisostere imidazole of the first generation Grp94‐selective inhibitors were pursued to develop more potent and selective Grp94 inhibitors. Reduction of the angle between the resorcinol moiety and the benzyl side chain of BnIm led to a product that exhibited improved Grp94 affinity and selectivity. KUNG65 (30 ) exhibited nanomolar anti‐migratory activity against aggressive and metastatic cancers.