Improved Scalable Synthesis of Clinical Candidate KZR‐616, a Selective Immunoproteasome Inhibitor

Abstract KZR‐616 is a selective immunoproteasome inhibitor that is under clinical evaluation for the treatment of Systemic Lupus Erythematosus (SLE). KZR‐616 represents a first‐in‐class drug candidate for the treatment of autoimmune diseases targeting the immunoproteasome. Laboratory replication of the published synthetic route of KZR‐616 resulted in an inseparable mixture of enantiomers and diastereomers. Herein, we describe a stereoselective and scalable synthetic pathway for KZR‐616 that avoids laborious separation of enantiomeric mixtures of amino acids. Moreover, the new route provides KZR‐616 in higher overall yield (42.8 %), did not require a chiral chromatographic purification step, and the final product was obtained in high purity. The synthesized compound was evaluated for inhibition of human immunoproteasome and constitutive proteasome and found to target the β1 and β5 subunits of the immunoproteasome with higher potency than the equivalent subunits of the constitutive proteasome. Therefore, we have confirmed that KZR‐616, synthesized using this new method, is an immunoproteasome selective inhibitor.