Small molecules for impairing endoplasmic reticulum in cancer

The endoplasmic reticulum plays an important role in maintaining the protein homeostasis of cells as well as regulating Ca²⁺ storage. An increased load of unfolded proteins in the endoplasmic reticulum due to alterations in the cell's metabolic pathway leads to the activation of the unfolded protein response, also known as ER stress. ER stress plays a major role in maintaining the growth and survival of various cancer cells, but persistent ER stress can also lead to cell death and hence can be a therapeutic pathway in the treatment of cancer. In this review, we focus on different types of small molecules that impair different ER stress sensors, the protein degradation machinery, and chaperone proteins. We also review the metal complexes and other miscellaneous compounds inducing ER stress through multiple mechanisms. Finally, we discuss the challenges in this emerging area of research and the potential direction of research to overcome them towards next-generation ER-targeted cancer therapy.