Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions

Tim J. Blackburn; Shafiq Ahmed; Christopher R. Coxon; Junfeng Liu; Xiaohong Lu; Bernard T. Golding; Roger J. Griffin; Claire Hutton; David R. Newell; Stephen Ojo; Anna F. Watson; Andrey Zaytzev; Yan Zhao; John Lunec; Ian R. Hardcastle

doi:10.1039/c3md00161j

Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions

Tim J. Blackburn
, Shafiq Ahmed
, Christopher R. Coxon
, Junfeng Liu
, Xiaohong Lu
, Bernard T. Golding
, Roger J. Griffin
, Claire Hutton
, David R. Newell
, Stephen Ojo
, Anna F. Watson
, Andrey Zaytzev
, Yan Zhao
, John Lunec^*
, Ian R. Hardcastle

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

91 Downloads (Pure)

Abstract

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC₅₀ = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5- diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC₅₀ = 0.11 μM; MDMX IC₅₀ = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H, 3H,5H)-trione (MDM2 IC₅₀ = 0.15 μM; MDMX IC₅₀ = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.

Original language	English
Pages (from-to)	1297-1304
Number of pages	8
Journal	MedChemComm
Volume	4
Issue number	9
DOIs	https://doi.org/10.1039/c3md00161j
Publication status	Published - 1 Sept 2013

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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Blackburn, T. J., Ahmed, S., Coxon, C. R., Liu, J., Lu, X., Golding, B. T., Griffin, R. J., Hutton, C., Newell, D. R., Ojo, S., Watson, A. F., Zaytzev, A., Zhao, Y., Lunec, J., & Hardcastle, I. R. (2013). Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions. MedChemComm, 4(9), 1297-1304. https://doi.org/10.1039/c3md00161j

@article{655cc85aebed407ea681a5f9f50cf329,

title = "Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions",

abstract = "Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5- diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H, 3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.",

author = "Blackburn, \{Tim J.\} and Shafiq Ahmed and Coxon, \{Christopher R.\} and Junfeng Liu and Xiaohong Lu and Golding, \{Bernard T.\} and Griffin, \{Roger J.\} and Claire Hutton and Newell, \{David R.\} and Stephen Ojo and Watson, \{Anna F.\} and Andrey Zaytzev and Yan Zhao and John Lunec and Hardcastle, \{Ian R.\}",

year = "2013",

month = sep,

day = "1",

doi = "10.1039/c3md00161j",

language = "English",

volume = "4",

pages = "1297--1304",

journal = "MedChemComm",

issn = "2040-2503",

publisher = "Royal Society of Chemistry",

number = "9",

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TY - JOUR

T1 - Diaryl- and triaryl-pyrrole derivatives

T2 - Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions

AU - Blackburn, Tim J.

AU - Ahmed, Shafiq

AU - Coxon, Christopher R.

AU - Liu, Junfeng

AU - Lu, Xiaohong

AU - Golding, Bernard T.

AU - Griffin, Roger J.

AU - Hutton, Claire

AU - Newell, David R.

AU - Ojo, Stephen

AU - Watson, Anna F.

AU - Zaytzev, Andrey

AU - Zhao, Yan

AU - Lunec, John

AU - Hardcastle, Ian R.

PY - 2013/9/1

Y1 - 2013/9/1

N2 - Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5- diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H, 3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.

AB - Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5- diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H, 3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.

UR - https://www.scopus.com/pages/publications/84883037372

U2 - 10.1039/c3md00161j

DO - 10.1039/c3md00161j

M3 - Article

AN - SCOPUS:84883037372

SN - 2040-2503

VL - 4

SP - 1297

EP - 1304

JO - MedChemComm

JF - MedChemComm

IS - 9

ER -

Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions

Abstract

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