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
  • 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.