Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP

Yan Jia, Ting Lan Chiu, Elizabeth A. Amin, Vitaly Polunovsky, Peter B. Bitterman, Carston R. Wagner

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N7-benzylated guanosine monophosphate (Bn7-GMP) for eIF4E, we virtually screened a library of 80 Bn7-GMP analogs utilizing CombiGlide as implemented in Schrodinger®. A subset library of substituted Bn7-GMP analogs was synthesized and their dissociation constants (Kd) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.

Original languageEnglish (US)
Pages (from-to)1304-1313
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number4
DOIs
StatePublished - Apr 1 2010

Fingerprint

Peptide Initiation Factors
Guanosine Monophosphate
Quantitative Structure-Activity Relationship
Libraries
RNA Cap-Binding Proteins
Guanosine
Drug Discovery
Structure-Activity Relationship
Neoplasms
X-Rays
X rays
Messenger RNA

Keywords

  • Anticancer
  • Antifibrotic
  • CoMFA
  • CoMSIA
  • Translation initiation
  • eIF4E

Cite this

Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP. / Jia, Yan; Chiu, Ting Lan; Amin, Elizabeth A.; Polunovsky, Vitaly; Bitterman, Peter B.; Wagner, Carston R.

In: European Journal of Medicinal Chemistry, Vol. 45, No. 4, 01.04.2010, p. 1304-1313.

Research output: Contribution to journalArticle

@article{1c76be3302614a518b2d9be18f6db95f,
title = "Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP",
abstract = "Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N7-benzylated guanosine monophosphate (Bn7-GMP) for eIF4E, we virtually screened a library of 80 Bn7-GMP analogs utilizing CombiGlide as implemented in Schrodinger{\circledR}. A subset library of substituted Bn7-GMP analogs was synthesized and their dissociation constants (Kd) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.",
keywords = "Anticancer, Antifibrotic, CoMFA, CoMSIA, Translation initiation, eIF4E",
author = "Yan Jia and Chiu, {Ting Lan} and Amin, {Elizabeth A.} and Vitaly Polunovsky and Bitterman, {Peter B.} and Wagner, {Carston R.}",
year = "2010",
month = "4",
day = "1",
doi = "10.1016/j.ejmech.2009.11.054",
language = "English (US)",
volume = "45",
pages = "1304--1313",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "4",

}

TY - JOUR

T1 - Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP

AU - Jia, Yan

AU - Chiu, Ting Lan

AU - Amin, Elizabeth A.

AU - Polunovsky, Vitaly

AU - Bitterman, Peter B.

AU - Wagner, Carston R.

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N7-benzylated guanosine monophosphate (Bn7-GMP) for eIF4E, we virtually screened a library of 80 Bn7-GMP analogs utilizing CombiGlide as implemented in Schrodinger®. A subset library of substituted Bn7-GMP analogs was synthesized and their dissociation constants (Kd) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.

AB - Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N7-benzylated guanosine monophosphate (Bn7-GMP) for eIF4E, we virtually screened a library of 80 Bn7-GMP analogs utilizing CombiGlide as implemented in Schrodinger®. A subset library of substituted Bn7-GMP analogs was synthesized and their dissociation constants (Kd) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.

KW - Anticancer

KW - Antifibrotic

KW - CoMFA

KW - CoMSIA

KW - Translation initiation

KW - eIF4E

UR - http://www.scopus.com/inward/record.url?scp=77349115916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77349115916&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2009.11.054

DO - 10.1016/j.ejmech.2009.11.054

M3 - Article

VL - 45

SP - 1304

EP - 1313

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

IS - 4

ER -