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