NMS-E194

NMS-E194 is a potent and selective ATP-competitive inhibitor of PKR-like endoplasmic reticulum kinase (PERK), also known as EIF2AK3, belonging to the arylsulfonamide chemical class. Developed by Nerviano Medical Sciences, it targets the Unfolded Protein Response (UPR), a signaling network essential for protein homeostasis in the endoplasmic reticulum. Multiple myeloma and other protein-secreting tumors are highly dependent on the UPR for survival, making PERK an attractive therapeutic target. NMS-E194 exhibits a unique bi-phasic behavior in vitro: at low nanomolar doses, it activates PERK signaling (causing ATF4 accumulation), while at concentrations exceeding 200 nM, it inhibits the kinase and its downstream pathways, leading to apoptosis. In preclinical models, NMS-E194 demonstrated significant anti-tumor activity following oral administration in multiple myeloma (KMS-11) and diffuse large B-cell lymphoma cell lines, with a favorable pharmacokinetic profile in mice.