LTI6426

LTI6426 is a first-in-class, orally bioavailable small molecule inhibitor of protein disulfide isomerase (PDI), developed for enhanced anti-cancer activity in multiple myeloma. It displays potent synergy with proteasome inhibitors (such as bortezomib and carfilzomib) and histone deacetylase inhibitors (HDACi, such as panobinostat), but not all classes of epigenetic drugs. LTI6426 sensitizes multiple myeloma cells to HDAC inhibition and drives cell death by converging on endoplasmic reticulum (ER) stress response pathways, specifically activating ATF3, DDIT3/CHOP, and DNAJB1. Its preclinical development highlights reduced toxicity of panobinostat in combination compared to panobinostat monotherapy, especially in proteasome inhibitor-resistant myeloma models[1][2][5][7][8].