Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors.

Stefaniak J., Lewis AM., Conole D., Galan SRG., Bataille CJR., Wynne GM., Castaldi MP., Lundbäck T., Russell AJ., Huber KVM.

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.

DOI

10.1021/acschembio.8b00665

Type

Journal article

Journal

ACS Chem Biol

Publication Date

19/10/2018

Volume

13

Pages

2849 - 2854

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