molecules of the month


covalent immunoproteasome inhibitor

subcutaneous agent in Ph. I/II for SLE and LN

designed from proteasome inhibitors

Drug Metabolism and Disposition

Kezar Life Sciences, San Francisco, US

Chemical structure of KZR-616 Kezar Life Sciences covalent immunoproteasome inhibitor
1 min read

The Kezar Life Sciences covalent immunoproteasome inhibitor, KZR-616, licensed from Onyx, targets the LMP7 and LMP2 active sites of the immunoproteasome, and is currently in Ph. II trials for autoimmune disorders (30 mg SC QW for 2 weeks, then 45 mg SC weekly for 14 weeks). More subunit-selective, proteasome-sparing reversible-covalent LMP7 inhibitors (including Molecule of the Month M3258and these examples) have recently been reported but are not being developed in autoimmune diseases. Interestingly, the molecule’s epoxide is primarily metabolized by microsomal epoxide hydrolase (mEH), and not CYPs or soluble epoxide hydrolase (sEH) as might be expected, adding complexity to PK prediction. Though KZR-616 was disclosed a few years ago, this article is a nice case study for how to distinguish metabolic routes of an epoxide-containing…

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