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ACS Chem Biol. 2018 Oct 19;13(10):2849-2854. doi: 10.1021/acschembio.8b00665. Epub 2018 Sep 19.

Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors.

Author information

1
Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , Oxford , United Kingdom.
2
Target Discovery Institute, Nuffield Department of Medicine , University of Oxford , Oxford , United Kingdom.
3
Department of Chemistry, Chemistry Research Laboratory , University of Oxford , Oxford , United Kingdom.
4
Department of Pharmacology , University of Oxford , Oxford , United Kingdom.
5
Discovery Sciences, IMED Biotech Unit , AstraZeneca , Waltham , Massachusetts 02451 , United States.
6
Discovery Sciences, IMED Biotech Unit , AstraZeneca , Gothenburg , Sweden.

Abstract

Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes.

PMID:
30216042
PMCID:
PMC6198280
DOI:
10.1021/acschembio.8b00665
[Indexed for MEDLINE]
Free PMC Article

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