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Journal of Medical Oncology and Therapeutics | Volume: 3
July 23-25, 2018 | Moscow, Russia
12
th
World Cancer Congress
Discovery and development of dual inhibitors of MDM2 and XIAP
Muxiang Zhou
1
, Lubing Gu
2
, Tao Liu
and
Sha Yi
Emory University School of Medicine, USA
M
DM2 and XIAP promote cancer cell survival by inhibiting p53
and 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, increaseMDM2 protein expression, and enhance
resistance to apoptosis. We hypothesized that disrupting the
interaction between MDM2 and
XIAP
would decrease expression
of bothproteins andenhance 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
selectedfor further study (MX3,MX11, andMX69) reducedprotein
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 anMDM2-, p53-, and XIAP-dependentmanner.MX69
had little effect on normal hematopoiesis, and was thus tested in
vivo inmicebearingALL xenografts. TreatmentwithMX69 reduced
disease burden, increased survival, andwas well tolerated inmice.
Altogether, these findings support further investigation of MX69
and its analogs as therapies to induce apoptosis in cancer cells.
Speaker Biography
Muxiang Zhou research is in the field of signaling pathway identification and molecular
targeting of pediatric cancers. He have a broad background in molecular biology of
childhood cancer and longstanding interest in understanding the role of several
oncoproteins such as MDM2 and XIAP in mediating cancer cell promotion and
resistance to anticancer treatment. His current research programs build logically on my
previous work, translating basic studies on MDM2 and XIAP-mediated signaling into
first preclinical and later a clinical investigation of small molecule inhibitors targeting
MDM2 and XIAP for use as novel cancer treatments.
e:
mzhou@emory.edu