title: 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.
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.
authors.affiliation: Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge, MA 02139, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Cynthia
authors.initials: C
authors.lastname: Barrett
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Blank
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruzzese
authors.forename: Nancy
authors.initials: N
authors.lastname: Bump
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Dick
authors.forename: Paul
authors.initials: P
authors.lastname: Fleming
authors.forename: Khristofer
authors.initials: K
authors.lastname: Garcia
authors.forename: Paul
authors.initials: P
authors.lastname: Hales
authors.forename: Zhigen
authors.initials: Z
authors.lastname: Hu
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.forename: Jane X
authors.initials: JX
authors.lastname: Liu
authors.forename: Darshan S
authors.initials: DS
authors.lastname: Sappal
authors.forename: Michael D
authors.initials: MD
authors.lastname: Sintchak
authors.forename: Christopher
authors.initials: C
authors.lastname: Tsu
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Gigstad
mesh_terms: D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D013912:Threonine; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex