HM100168

HM100168 is a potent, selective, and covalent small molecule inhibitor of the endoribonuclease (RNase) activity of inositol-requiring enzyme 1α (IRE1α), developed by Hanmi Pharmaceutical. It features a hydroxy-aryl-aldehyde (HAA) moiety that binds covalently to the lysine 907 (K907) residue within the RNase catalytic site of IRE1α, specifically blocking its endonuclease activity without affecting its kinase activity. By inhibiting the IRE1α-XBP1 pathway, HM100168 suppresses the generation of spliced XBP1 (XBP1s), thereby disrupting protein folding homeostasis and the unfolded protein response (UPR) under endoplasmic reticulum (ER) stress. HM100168 is being investigated as a potential therapeutic strategy for solid cancers, including breast cancer, and has demonstrated synergistic anti-tumor efficacy when combined with other anti-tumorigenic agents (such as taxane chemotherapy and KRAS inhibitors) to overcome drug resistance.