Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis

Donna Petch, Rosaleen J. Anderson, Anne Cunningham, Suja E. George, David E. Hibbs, Ran Liu, Simon P. Mackay, Andrew Paul, David A. P. Small, Paul W. Groundwater

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS3 chemical crosslinking assay). 7-Benzyl-8-{N'-[1-( 3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 mu M) leads to 37% inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V-FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis.

LanguageEnglish
Pages5901-5914
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number19
Early online date7 Aug 2012
DOIs
Publication statusPublished - 1 Oct 2012

Fingerprint

Dimerization
Keratinocytes
Psoriasis
Assays
Charge coupled devices
Anthralin
Caspase 7
Cell Line
U937 Cells
Xanthine
MAP Kinase Signaling System
Fluorescein-5-isothiocyanate
Annexin A5
Cells
Theophylline
Lead compounds
Oxidants
Caspase 3
Computer Simulation
Phosphorylation

Keywords

  • anti-proliferative
  • EGFR dimerization inhibitors
  • treatment of psoriasis
  • xanthines
  • apoptosis

Cite this

Petch, D., Anderson, R. J., Cunningham, A., George, S. E., Hibbs, D. E., Liu, R., ... Groundwater, P. W. (2012). Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis. Bioorganic and Medicinal Chemistry, 20(19), 5901-5914. https://doi.org/10.1016/j.bmc.2012.07.048
Petch, Donna ; Anderson, Rosaleen J. ; Cunningham, Anne ; George, Suja E. ; Hibbs, David E. ; Liu, Ran ; Mackay, Simon P. ; Paul, Andrew ; Small, David A. P. ; Groundwater, Paul W. / Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 19. pp. 5901-5914.
@article{5463934bf228456ea7c152c691714351,
title = "Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis",
abstract = "Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS3 chemical crosslinking assay). 7-Benzyl-8-{N'-[1-( 3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 mu M) leads to 37{\%} inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V-FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis.",
keywords = "anti-proliferative, EGFR dimerization inhibitors, treatment of psoriasis, xanthines, apoptosis",
author = "Donna Petch and Anderson, {Rosaleen J.} and Anne Cunningham and George, {Suja E.} and Hibbs, {David E.} and Ran Liu and Mackay, {Simon P.} and Andrew Paul and Small, {David A. P.} and Groundwater, {Paul W.}",
year = "2012",
month = "10",
day = "1",
doi = "10.1016/j.bmc.2012.07.048",
language = "English",
volume = "20",
pages = "5901--5914",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
number = "19",

}

Petch, D, Anderson, RJ, Cunningham, A, George, SE, Hibbs, DE, Liu, R, Mackay, SP, Paul, A, Small, DAP & Groundwater, PW 2012, 'Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis' Bioorganic and Medicinal Chemistry, vol. 20, no. 19, pp. 5901-5914. https://doi.org/10.1016/j.bmc.2012.07.048

Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis. / Petch, Donna; Anderson, Rosaleen J.; Cunningham, Anne; George, Suja E.; Hibbs, David E.; Liu, Ran; Mackay, Simon P.; Paul, Andrew; Small, David A. P.; Groundwater, Paul W.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 19, 01.10.2012, p. 5901-5914.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis

AU - Petch, Donna

AU - Anderson, Rosaleen J.

AU - Cunningham, Anne

AU - George, Suja E.

AU - Hibbs, David E.

AU - Liu, Ran

AU - Mackay, Simon P.

AU - Paul, Andrew

AU - Small, David A. P.

AU - Groundwater, Paul W.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS3 chemical crosslinking assay). 7-Benzyl-8-{N'-[1-( 3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 mu M) leads to 37% inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V-FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis.

AB - Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS3 chemical crosslinking assay). 7-Benzyl-8-{N'-[1-( 3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 mu M) leads to 37% inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V-FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis.

KW - anti-proliferative

KW - EGFR dimerization inhibitors

KW - treatment of psoriasis

KW - xanthines

KW - apoptosis

UR - http://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry

U2 - 10.1016/j.bmc.2012.07.048

DO - 10.1016/j.bmc.2012.07.048

M3 - Article

VL - 20

SP - 5901

EP - 5914

JO - Bioorganic and Medicinal Chemistry

T2 - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 19

ER -