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

Abstract : 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.
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Submitted on : Wednesday, April 25, 2018 - 2:54:19 PM
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Richy et al_Structure-based de...
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N. Richy, D. Sarraf, X. Maréchal, N. Janmamode, Ronan Le Guével, et al.. Structure-based design of human immuno- and constitutive proteasomes inhibitors. European Journal of Medicinal Chemistry, Elsevier, 2018, 145, pp.570-587. ⟨10.1016/j.ejmech.2018.01.013⟩. ⟨hal-01713510⟩



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