Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	30	4	2016 Oct 10	623-636	Cancer Cell

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 23	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	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
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