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Ref Type Journal Article
PMID (27666947)
Authors Gu L, Zhang H, Liu T, Zhou S, Du Y, Xiong J, Yi S, Qu CK, Fu H, Zhou M
Title Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment.
URL
Abstract Text MDM2 and XIAP are mutually regulated. Binding of MDM2 RING protein to the IRES region on XIAP mRNA results in MDM2 protein stabilization and enhanced XIAP translation. In this study, we developed a protein-RNA fluorescence polarization (FP) assay for high-throughput screening (HTS) of chemical libraries. Our FP-HTS identified eight inhibitors that blocked the MDM2 protein-XIAP RNA interaction, leading to MDM2 degradation. The compound-induced MDM2 downregulation resulted not only in inhibition of XIAP expression, but also in activation of p53, which contributed to cancer cell apoptosis in vitro and inhibition of cancer cell proliferation in vivo. Importantly, one of the MDM2/XIAP inhibitors, MX69, showed minimal inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in animal models.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MX69 MX69 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MX69 MX-69 MDM2 Inhibitor 22 MX69 is an inhibitor of the interaction between MDM2 and XIAP, which results in MDM2 degradation and subsequent repression of TP53 activation thereby possibly leading to antitumor activity (PMID: 27666947).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MDM2 over exp TP53 wild-type neuroblastoma sensitive MX69 Preclinical - Cell culture Actionable In a preclinical study, a neuroblastoma cell line over expressing MDM2 and wild-type for TP53 demonstrated sensitivity to treatment with MX69 in culture, resulting in decreased cell survival (PMID: 27666947). 27666947
MDM2 over exp TP53 wild-type acute lymphoblastic leukemia sensitive MX69 Preclinical - Cell line xenograft Actionable In a preclinical study, MX69 treatment induced cell death and inhibited cell growth in a TP53 wild-type acute lymphocytic leukemia cell line over expressing MDM2, and prolonged survival in xenograft models (PMID: 27666947). 27666947