6AOL

Structure of molecular chaperone Grp94 bound to selective inhibitor methyl 3-chloro-2-(2-{2-[(4-fluorophenyl)methyl]phenyl}ethyl)-4,6-dihydroxybenzoate

Summary for 6AOL

• Entry DOI: 10.2210/pdb6aol/pdb
• Descriptor: Endoplasmin, methyl 3-chloro-2-(2-{2-[(4-fluorophenyl)methyl]phenyl}ethyl)-4,6-dihydroxybenzoate, 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL, ... (4 entities in total)
• Functional Keywords: grp94, hsp90, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Canis lupus familiaris (Dog); More
• Cellular location: Endoplasmic reticulum lumen: P41148
• Total number of polymer chains: 1
• Total formula weight: 27908.00

Authors

Lieberman, R.L.,Huard, D.J.E. (deposition date: 2017-08-16, release date: 2017-10-11, Last modification date: 2023-10-04)

Primary citation

Crowley, V.M.,Huard, D.J.E.,Lieberman, R.L.,Blagg, B.S.J.
Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer.
Chemistry, 23:15775-15782, 2017

PubMed 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 compound 30, 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 inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.

PubMed: 28857290
DOI: 10.1002/chem.201703398

Experimental method

X-RAY DIFFRACTION (2.764 Å)