2. Academic Validation
  3. Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit

  • ACS Med Chem Lett. 2017 Mar 9;8(4):413-417. doi: 10.1021/acsmedchemlett.6b00496.
Henry W B Johnson 1,  Janet L Anderl 1,  Erin K Bradley 2,  John Bui 2,  Jeffrey Jones 2,  Shirin Arastu-Kapur 2,  Lisa M Kelly 2,  Eric Lowe 1,  David C Moebius 2,  Tony Muchamuel 1,  Christopher Kirk 1,  Zhengping Wang 2,  Dustin McMinn 1
Affiliations

Affiliations

  • 1 Kezar Life Sciences, 300 Utah Avenue, Suite 105, South San Francisco, California 94080, United States.
  • 2 Onyx Pharmaceuticals, An Amgen Subsidiary, 249 East Grand Avenue, South San Francisco, California 94080, United States.
PMID: 28435528 DOI: 10.1021/acsmedchemlett.6b00496
Abstract

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor KZR-504 (12).

Keywords

LMP2; constitutive proteasome; immunoproteasome; β1c; β1i.

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