Journal of Medicinal Chemistry p. 11127 - 11143 (2018)
Update date:2022-08-05
Topics:
Johnson, Henry W.B.
Lowe, Eric
Anderl, Janet L.
Fan, Andrea
Muchamuel, Tony
Bowers, Simeon
Moebius, David C.
Kirk, Christopher
McMinn, Dustin L.
Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.
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