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

Christopher Blackburn; 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

doi:10.1016/j.bmcl.2010.09.032

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

Christopher Blackburn
, 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

Millennium Pharmaceuticals Inc.

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	6581-6586
Number of pages	6
Journal	Bioorganic & medicinal chemistry letters
Volume	20
Issue number	22
Early online date	15 Sept 2010
DOIs	https://doi.org/10.1016/j.bmcl.2010.09.032
Publication status	Published - 15 Nov 2010
Externally published	Yes

Keywords

Chymotrypsin/antagonists & inhibitors
Dipeptides/chemistry
Humans
Models, Molecular
Proteasome Endopeptidase Complex/metabolism
Threonine/chemistry

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10.1016/j.bmcl.2010.09.032

Cite this

Blackburn, C., Barrett, C., Blank, J. L., Bruzzese, F. J., Bump, N., Dick, L. R., Fleming, P., Garcia, K., Hales, P., Hu, Z., Jones, M., Liu, J. X., Sappal, D. S., Sintchak, M. D., Tsu, C., & Gigstad, K. M. (2010). 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. Bioorganic & medicinal chemistry letters, 20(22), 6581-6586. https://doi.org/10.1016/j.bmcl.2010.09.032

@article{ffafba9693c64a9395381c60993def07,

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.",

keywords = "Chymotrypsin/antagonists \& inhibitors, Dipeptides/chemistry, Humans, Models, Molecular, Proteasome Endopeptidase Complex/metabolism, Threonine/chemistry",

author = "Christopher Blackburn and Cynthia Barrett and Blank, \{Jonathan L\} and Bruzzese, \{Frank J\} and Nancy Bump and Dick, \{Lawrence R\} and Paul Fleming and Khristofer Garcia and Paul Hales and Zhigen Hu and Matthew Jones and Liu, \{Jane X\} and Sappal, \{Darshan S\} and Sintchak, \{Michael D\} and Christopher Tsu and Gigstad, \{Kenneth M\}",

year = "2010",

month = nov,

day = "15",

doi = "10.1016/j.bmcl.2010.09.032",

language = "English",

volume = "20",

pages = "6581--6586",

journal = "Bioorganic \& medicinal chemistry letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "22",

}

Blackburn, C, Barrett, C, Blank, JL, Bruzzese, FJ, Bump, N, Dick, LR, Fleming, P, Garcia, K, Hales, P, Hu, Z, Jones, M, Liu, JX, Sappal, DS, Sintchak, MD, Tsu, C & Gigstad, KM 2010, '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', Bioorganic & medicinal chemistry letters, vol. 20, no. 22, pp. 6581-6586. https://doi.org/10.1016/j.bmcl.2010.09.032

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. / Blackburn, Christopher; Barrett, Cynthia; Blank, Jonathan L et al.
In: Bioorganic & medicinal chemistry letters, Vol. 20, No. 22, 15.11.2010, p. 6581-6586.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Blackburn, Christopher

AU - Barrett, Cynthia

AU - Blank, Jonathan L

AU - Bruzzese, Frank J

AU - Bump, Nancy

AU - Dick, Lawrence R

AU - Fleming, Paul

AU - Garcia, Khristofer

AU - Hales, Paul

AU - Hu, Zhigen

AU - Jones, Matthew

AU - Liu, Jane X

AU - Sappal, Darshan S

AU - Sintchak, Michael D

AU - Tsu, Christopher

AU - Gigstad, Kenneth M

PY - 2010/11/15

Y1 - 2010/11/15

N2 - 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.

AB - 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.

KW - Chymotrypsin/antagonists & inhibitors

KW - Dipeptides/chemistry

KW - Humans

KW - Models, Molecular

KW - Proteasome Endopeptidase Complex/metabolism

KW - Threonine/chemistry

U2 - 10.1016/j.bmcl.2010.09.032

DO - 10.1016/j.bmcl.2010.09.032

M3 - Article

C2 - 20875739

SN - 0960-894X

VL - 20

SP - 6581

EP - 6586

JO - Bioorganic & medicinal chemistry letters

JF - Bioorganic & medicinal chemistry letters

IS - 22

ER -

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

Keywords

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