Approximately 50% of human tumors express wild type p53 that is functionally compromised due to defectsin regulation. P53 level and activity is regulated by MDM2 and MDMX. MDM2 is a validated drug target andnovel inhibitors are being developed, including the recently reported MDM2/p53 binding disrupter Nutlin 3.MDMX is frequently overexpressed in tumors, but its significance in p53 inactivation is relatively unknown.We found that MDMX is an important regulator of p53 response to abnormal ribosomal biogenesis. P53activation by ribosomal stress agents such as Actinomycin D (Act.D) and 5-fluorouracil (5-FU) requiresdown-regulation of MDMX by accelerated degradation. Tumor cells overexpressing MDMX are less sensitiveto Act.D and 5-FU-induced growth arrest, whereas knockdown of MDMX increases sensitivity to ribosomalstress and abrogates tumor formation in nude mice. Surprisingly, Nutlin 3 does not disrupt p53-MDMXbinding and functions inefficiently in MDMX overexpressing cells, suggesting a need to develop MDMX-specific or MDM2 and MDMX dual inhibitors. We hypothesize that both MDM2 and MDMX are importanttargets in cancer treatment due to their shared and distinct functional characteristics. Development of novelMDM2 and MDMX inhibitors are necessary for validating the therapeutic potential of targeting both MDM2and MDMX-P53 interactions. We propose the following aims to test these hypotheses. (1)Investigate therole and mechanism of MDMX in tumor formation. (2) Structure-based rational design of inhibitors ofMDM2 and MDMX-p53 interaction. (3) Synthesis of focused chemical libraries based on leadcompounds. (4) Evaluate compounds for p53 activation and anti-tumor activity. These experimentsshould validate MDMX as a drug target and may provide lead compounds for further development ofexperimental drugs against MDM2 and MDMX.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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H. Lee Moffitt Cancer Center & Research Institute
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