InterfERing with endoplasmic reticulum stress.

Stress to the endoplasmic reticulum (ER) is a recognized factor in Alzheimer's and Parkinson's diseases, diabetes, heart disease, liver disorders and cancer. Thus, drugs that interfere with ER stress have wide therapeutic potential. Here we review the effects of drugs on three arms of ER stress: the protein kinase RNA-activated (PKR)-like ER kinase (PERK) arm, the activated transcription factor 6 (ATF6) arm and the inositol-requiring enzyme 1 (IRE1) arm. Drugs fall into five groups: (i) compounds directly binding to ER stress molecules; (ii) chemical chaperones; (iii) inhibitors of protein degradation; (iv) antioxidants; (v) drugs affecting calcium signaling. Treatments are generally inhibitory and lead to increased viability, except when applied to cancer cells. A focus on interfering with the ATF6 arm is required, and more in vivo testing of these compounds concurrently across all three arms is needed if the full importance of ER stress to human disease is to be realized.