Structure-based design of human immuno- and constitutive proteasomes inhibitors

N. Richy (1) , D. Sarraf (1) , X. Maréchal (2) , N. Janmamode (1) , E. Genin (1) , M. Reboud-Ravaux (3) , J. Vidal (1) , Rémy Le Guével

1 ISCR - Institut des Sciences Chimiques de Rennes
2 B2A - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing
3 VCII - Vieillissement Cellulaire Intégré et Inflammation

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.

Keywords: 3-HydroxyOxindolylalanine derivatives; Constitutive proteasome; Immunoproteasome; Proteasome inhibitors; Tryptophan oxidation

Domains: Chemical Sciences; Chemical Sciences; Organic chemistry

N. Richy, D. Sarraf, X. Maréchal, N. Janmamode, E. Genin, et al.. Structure-based design of human immuno- and constitutive proteasomes inhibitors. European Journal of Medicinal Chemistry, 2018, 145, pp.570-587. ⟨10.1016/j.ejmech.2018.01.013⟩. ⟨hal-01713510⟩