Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer.
Vincent M CrowleyDustin J E HuardRaquel L LiebermanBrian S J BlaggPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2017)
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.
Keyphrases
- heat shock protein
- endoplasmic reticulum stress
- cell surface
- endoplasmic reticulum
- squamous cell carcinoma
- small cell lung cancer
- heat shock
- structure activity relationship
- small molecule
- stem cells
- type diabetes
- staphylococcus aureus
- oxidative stress
- escherichia coli
- binding protein
- skeletal muscle
- young adults
- blood pressure
- biofilm formation
- photodynamic therapy
- cystic fibrosis
- pseudomonas aeruginosa
- protein protein
- combination therapy
- insulin resistance
- mass spectrometry
- childhood cancer
- structural basis
- emergency medicine
- smoking cessation