Characterization of Binding Interactions Between Small Molecule SJ-172550 and MDMX, an Important Regulator of the p53 Pathway

The p53 pathway is the most commonly disrupted pathway in cancer cells. Deregulation of this pathway can typically be traced to either mutations on the p53 gene itself or mutations on genes that modulate the p53 pathway. A prevalent interruption of the pathway, for tumors that express wild-type p53, is caused by the over expression of MDMX, a negative regulator of p53.  The small molecule SJ-172550 has been documented to be a MDMX inhibitor. However, the binding interaction between SJ-172550 and MDMX has not been well characterized. Understanding this biochemical interaction is essential for the optimization and development of pharmacologically relevant MDMX inhibitors. Through the use of a Fluorescence Polarization Assay and an Isothermal Denaturation Assay it was determined that the inhibition of MDMX by SJ-172550 occurs through a covalent modification of the protein. Therefore, it was concluded that SJ-172550 is not a good chemical scaffold for the development and optimization of other MDMX inhibitors.