Journal
MEDCHEMCOMM
Volume 4, Issue 9, Pages 1297-1304Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3md00161j
Keywords
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Funding
- Cancer Research UK
- EU FP6 DeP-PICT
- Cancer Research UK [15751] Funding Source: researchfish
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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 mu M). 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 mu M; MDMX IC50 -4.2 mu M) 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 mu M; MDMX IC50 = 4.2 mu M), 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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