Tethering small molecules to a phage display library

Discovery of a selective bivalent inhibitor of protein kinase A

Scott C. Meyer, Carolyn D. Shomin, Thomas Gaj, Indraneel Ghosh

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.

Original languageEnglish (US)
Pages (from-to)13812-13813
Number of pages2
JournalJournal of the American Chemical Society
Volume129
Issue number45
DOIs
StatePublished - Nov 14 2007

Fingerprint

Cyclic Peptides
Bacteriophages
Staurosporine
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Libraries
Display devices
Ligands
Proteins
Peptide Library
Molecules
Catalytic Domain
Phosphotransferases
Derivatives

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Tethering small molecules to a phage display library : Discovery of a selective bivalent inhibitor of protein kinase A. / Meyer, Scott C.; Shomin, Carolyn D.; Gaj, Thomas; Ghosh, Indraneel.

In: Journal of the American Chemical Society, Vol. 129, No. 45, 14.11.2007, p. 13812-13813.

Research output: Contribution to journalArticle

@article{95084203772744a5b85b5cb580eb93c9,
title = "Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A",
abstract = "We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.",
author = "Meyer, {Scott C.} and Shomin, {Carolyn D.} and Thomas Gaj and Indraneel Ghosh",
year = "2007",
month = "11",
day = "14",
doi = "10.1021/ja076197d",
language = "English (US)",
volume = "129",
pages = "13812--13813",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "45",

}

TY - JOUR

T1 - Tethering small molecules to a phage display library

T2 - Discovery of a selective bivalent inhibitor of protein kinase A

AU - Meyer, Scott C.

AU - Shomin, Carolyn D.

AU - Gaj, Thomas

AU - Ghosh, Indraneel

PY - 2007/11/14

Y1 - 2007/11/14

N2 - We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.

AB - We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.

UR - http://www.scopus.com/inward/record.url?scp=36148932151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36148932151&partnerID=8YFLogxK

U2 - 10.1021/ja076197d

DO - 10.1021/ja076197d

M3 - Article

VL - 129

SP - 13812

EP - 13813

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 45

ER -