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

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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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