2. Academic Validation
  3. Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome

Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome

  • Bioorg Med Chem Lett. 2010 Nov 15;20(22):6581-6. doi: 10.1016/j.bmcl.2010.09.032.
Christopher Blackburn 1,  Cynthia Barrett,  Jonathan L Blank,  Frank J Bruzzese,  Nancy Bump,  Lawrence R Dick,  Paul Fleming,  Khristofer Garcia,  Paul Hales,  Zhigen Hu,  Matthew Jones,  Jane X Liu,  Darshan S Sappal,  Michael D Sintchak,  Christopher Tsu,  Kenneth M Gigstad
Affiliations

Affiliation

  • 1 Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge, MA 02139, United States.
PMID: 20875739 DOI: 10.1016/j.bmcl.2010.09.032
Abstract

Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the Proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the β-5/6 active site of y20S. Derivative 25, (β5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the Proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.

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