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Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.

Figure 1
<div class='caption-title'>Synthesis of Compounds 68 and 71</div>
<div class='caption-title'>Synthesis of Compounds 74 and 77</div>
Xin BT, Huber EM, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev AF, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS
OpenAccess logo J Med Chem 62 1626-1642 (2019)

Cited: 11 times
EuropePMC logo PMID: 30657666

Abstract

Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.

Reviews citing this publication (3)

  1. Site-Specific Proteasome Inhibitors. Kisselev AF. Biomolecules 12 54 (2021)
  2. Immunoproteasome Function in Normal and Malignant Hematopoiesis. Tubío-Santamaría N, Ebstein F, Heidel FH, Krüger E. Cells 10 1577 (2021)
  3. A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential. Huber EM, Groll M. Cells 10 1929 (2021)

Articles citing this publication (8)

  1. Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome. Pawar A, Basler M, Goebel H, Alvarez Salinas GO, Groettrup M, Böttcher T. ACS Cent Sci 6 241-246 (2020)
  2. Syrbactin proteasome inhibitor TIR-199 overcomes bortezomib chemoresistance and inhibits multiple myeloma tumor growth in vivo. Pierce MR, Robinson RM, Ibarra-Rivera TR, Pirrung MC, Dolloff NG, Bachmann AS. Leuk Res 88 106271 (2020)
  3. Natural product scaffolds as inspiration for the design and synthesis of 20S human proteasome inhibitors. Hubbell GE, Tepe JJ. RSC Chem Biol 1 305-332 (2020)
  4. Preparative Method for Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid. Han J, Takeda R, Liu X, Konno H, Abe H, Hiramatsu T, Moriwaki H, Soloshonok VA. Molecules 24 E4521 (2019)
  5. A focused structure-activity relationship study of psoralen-based immunoproteasome inhibitors. Schiffrer ES, Sosič I, Šterman A, Mravljak J, Raščan IM, Gobec S, Gobec M. Medchemcomm 10 1958-1965 (2019)
  6. Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types. Larsson P, Pettersson D, Engqvist H, Werner Rönnerman E, Forssell-Aronsson E, Kovács A, Karlsson P, Helou K, Parris TZ. BMC Cancer 22 993 (2022)
  7. Structure-Based Design of Fluorogenic Substrates Selective for Human Proteasome Subunits. Maurits E, Degeling CG, Kisselev AF, Florea BI, Overkleeft HS. Chembiochem 21 3220-3224 (2020)
  8. Species-specific protein-protein interactions govern the humanization of the 20S proteasome in yeast. Sultana S, Abdullah M, Li J, Hochstrasser M, Kachroo AH. Genetics 225 iyad117 (2023)


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