Premium
The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery?
Author(s) -
McLaughlin Martin,
Vandenbroeck Koen
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01064.x
Subject(s) - geldanamycin , endoplasmic reticulum , unfolded protein response , hsp90 , drug discovery , chaperone (clinical) , protein folding , biology , small molecule , microbiology and biotechnology , heat shock protein , bioinformatics , biochemistry , medicine , pathology , gene
Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone‐ and stress‐related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease‐promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone‐mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER‐centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL‐12 family of cytokines by celecoxib and non‐coxib analogues.