Targeting inactive enzyme conformation: Aryl diketoacid derivatives as a new class of PTP1B inhibitors

Sijiu Liu, Li Fan Zeng, Li Wu, Xiao Yu, Ting Xue, Andrea M. Gunawan, Ya Qiu Long, Zhong-Yin Zhang

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.

Original languageEnglish
Pages (from-to)17075-17084
Number of pages10
JournalJournal of the American Chemical Society
Volume130
Issue number50
DOIs
StatePublished - Dec 17 2008

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Phosphatases
Conformations
Enzymes
Derivatives
Proteins
Catalytic Domain
Insulin
Drug Discovery
Medical problems
Amides
Dimers
Biological Availability
Hepatocellular Carcinoma
Permeability
Obesity
Crystal structure
Ligands
Pharmacology
Kinetics

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Targeting inactive enzyme conformation : Aryl diketoacid derivatives as a new class of PTP1B inhibitors. / Liu, Sijiu; Zeng, Li Fan; Wu, Li; Yu, Xiao; Xue, Ting; Gunawan, Andrea M.; Long, Ya Qiu; Zhang, Zhong-Yin.

In: Journal of the American Chemical Society, Vol. 130, No. 50, 17.12.2008, p. 17075-17084.

Research output: Contribution to journalArticle

Liu, Sijiu ; Zeng, Li Fan ; Wu, Li ; Yu, Xiao ; Xue, Ting ; Gunawan, Andrea M. ; Long, Ya Qiu ; Zhang, Zhong-Yin. / Targeting inactive enzyme conformation : Aryl diketoacid derivatives as a new class of PTP1B inhibitors. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 50. pp. 17075-17084.
@article{ee9852f3048e4358b62baa11befc3ef7,
title = "Targeting inactive enzyme conformation: Aryl diketoacid derivatives as a new class of PTP1B inhibitors",
abstract = "There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.",
author = "Sijiu Liu and Zeng, {Li Fan} and Li Wu and Xiao Yu and Ting Xue and Gunawan, {Andrea M.} and Long, {Ya Qiu} and Zhong-Yin Zhang",
year = "2008",
month = "12",
day = "17",
doi = "10.1021/ja8068177",
language = "English",
volume = "130",
pages = "17075--17084",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "50",

}

TY - JOUR

T1 - Targeting inactive enzyme conformation

T2 - Aryl diketoacid derivatives as a new class of PTP1B inhibitors

AU - Liu, Sijiu

AU - Zeng, Li Fan

AU - Wu, Li

AU - Yu, Xiao

AU - Xue, Ting

AU - Gunawan, Andrea M.

AU - Long, Ya Qiu

AU - Zhang, Zhong-Yin

PY - 2008/12/17

Y1 - 2008/12/17

N2 - There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.

AB - There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.

UR - http://www.scopus.com/inward/record.url?scp=58049206736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58049206736&partnerID=8YFLogxK

U2 - 10.1021/ja8068177

DO - 10.1021/ja8068177

M3 - Article

C2 - 19012396

AN - SCOPUS:58049206736

VL - 130

SP - 17075

EP - 17084

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 50

ER -