Structure-based design of human immuno- and constitutive proteasomes inhibitors
- Eur J Med Chem. 2018 Feb 10:145:570-587. doi: 10.1016/j.ejmech.2018.01.013.
- 1. Université Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes, Cedex, France.
- 2. Sorbonne Universités, UPMC Univ Paris 06-CNRS, IBPS, UMR 8256, Inserm ERL1164, B2A, 7 Quai Saint Bernard, F75005 Paris, France.
- 3. Université Rennes 1, Technology Platform ImPACcell, SFR UMS CNRS 3480, INSERM 018, Bâtiment 8, Campus de Villejean, 35043 Rennes, Cedex, France.
- 4. Sorbonne Universités, UPMC Univ Paris 06-CNRS, IBPS, UMR 8256, Inserm ERL1164, B2A, 7 Quai Saint Bernard, F75005 Paris, France. Electronic address: [email protected].
- 5. Université Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes, Cedex, France. Electronic address: [email protected].
Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S Proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive Proteasome and immunoproteasome acting at the nanomolar level (IC50 = 7.1 nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human Cancer cell lines.