Dual Inhibition of MDM2 and XIAP Induces Cancer Cell Apoptosis

MDM2 and X-linked inhibitor of apoptosis (XIAP) promote cancer cell survival by binding p53 and promoting its degradation and by inhibiting caspase activation to prevent apoptosis, respectively. Further, the RING domain of MDM2 can bind to the internal ribosome entry site (IRES) of XIAP mRNA transcripts to promote XIAP translation, increase MDM2 protein expression, and enhance resistance to apoptosis, suggesting a potential p53-independent role for MDM2 in enhancing cell survival. Gu and colleagues hypothesized that disrupting the interaction between MDM2 and XIAP would decrease expression of both proteins and enhance cancer cell apoptosis. A fluorescence polarization assay was developed for high-throughput screening of small-molecule inhibitors of XIAP IRES binding to the MDM2 RING domain. Of 141,394 small-molecule compounds tested, 8 candidates disrupted MDM2–XIAP binding, and 3 compounds selected for further study (MX3, MX11, and MX69) reduced protein expression of both MDM2 and XIAP when added to cancer cells. MX11 and MX69, which bound to the MDM2 RING, and MX3, which bound to the XIAP IRES, induced the self-ubiquitination and degradation of MDM2, which not only led to the stabilization and activation of p53 but also inhibited XIAP, resulting in activation of caspases 3, 7, and 9. In a panel of acute lymphoblastic leukemia (ALL) and neuroblastoma cell lines, MX3 and MX69 induced apoptosis in an MDM2-, p53-, and XIAP-dependent manner. MX69 had little effect on normal hematopoiesis, and was thus tested in vivo in mice bearing ALL xenografts. Treatment with MX69 reduced disease burden, increased survival, and was well tolerated in mice. Altogether, these findings support further investigation of MX69 and dual MDM2/XIAP inhibitors as therapies to induce apoptosis in cancer cells.

Gu L, Zhang H, Liu T, Zhou S, Du Y, Xiong J, et al. Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 2016;30:623–36.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.