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

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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

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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,

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doi = "10.1039/c3md00161j",

language = "English",

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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.

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VL - 4

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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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