Recent Advances in Small-Molecule Modulators Targeting IRE1α

IRE1α is an important ER stress sensor located on the ER membrane with dual kinase and ribonuclease activity. It plays a crucial role in restoring ER proteostasis and is associated with various human diseases. Targeting IRE1α has become a promising therapeutic approach. Many IRE1α modulators have been identified in recent years, and some of these have demonstrated excellent pre-clinical efficacy. The modulation of IRE1α RNase activity by small molecules can be achieved through two main mechanisms: directly binding to the RNase domain to block RNA splicing, or allosteric modulation of its activity through binding to the kinase domain. Apart from monovalent inhibitors and activators, proteolysis targeting chimeras have been reported to degrade IRE1α and block its downstream signalling by recruiting the E3 ligase-ubiquitin system. In this review we summarize the recent advances of targeting IRE1α with small molecules, including inhibitors, activators, and bifunctional molecules, providing an insight into future development of chemical modalities targeting IRE1α.