1620107-42-7Relevant academic research and scientific papers
Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)
Johnson, Henry W.B.,Lowe, Eric,Anderl, Janet L.,Fan, Andrea,Muchamuel, Tony,Bowers, Simeon,Moebius, David C.,Kirk, Christopher,McMinn, Dustin L.
, p. 11127 - 11143 (2019/01/04)
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.
DIPEPTIDE AND TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS
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Paragraph 00242; 00243; 00244; 00247, (2014/10/04)
Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.
Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes
De Bruin, Gerjan,Huber, Eva M.,Xin, Bo-Tao,Van Rooden, Eva J.,Al-Ayed, Karol,Kim, Kyung-Bo,Kisselev, Alexei F.,Driessen, Christoph,Van Der Stelt, Mario,Van Der Marel, Gijsbert A.,Groll, Michael,Overkleeft, Herman S.
, p. 6197 - 6209 (2014/08/18)
Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive r
