2. Academic Validation
  3. Modulation of proteasome subunit selectivity of syringolins

Modulation of proteasome subunit selectivity of syringolins

  • Bioorg Med Chem. 2024 May 15:106:117733. doi: 10.1016/j.bmc.2024.117733.
Kengo Tatsumi 1,  Shun Kitahata 1,  Yuya Komatani 1,  Akira Katsuyama 2,  Fumika Yakushiji 2,  Satoshi Ichikawa 3
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
  • 2 Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
  • 3 Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: ichikawa@pharm.hokudai.ac.jp.
PMID: 38704960 DOI: 10.1016/j.bmc.2024.117733
Abstract

Development of selective or dual Proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding β5 and β2 subunits.

Keywords

Anticancer; Natural product; Proteasome; Selectivity.

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