KZR-540

KZR-540 is a preclinical small molecule inhibitor of the Sec61 translocon, originally discovered by Kezar Life Sciences and acquired by Enodia Therapeutics in 2024. The Sec61 translocon is the primary channel responsible for the translocation of nascent polypeptides into the endoplasmic reticulum (ER). KZR-540 selectively blocks the biogenesis of specific secreted and transmembrane proteins by preventing their entry into the ER, which results in their misfolding and subsequent degradation by the cytosolic proteasome. This mechanism, often referred to as co-translational protein degradation, is being leveraged to target key drivers of inflammation, immunological disorders, and various cancers. As a follow-on candidate to KZR-261, KZR-540 represents a novel approach to targeted protein degradation (TPD) that does not rely on E3 ligase recruitment.